Quinoline derivatives

ABSTRACT

A novel compound of the formula: 
                 
 
wherein A, B, C, D, T, Y, and Z represent each methine or nitrogen; R 1,  R 2 , R 3 , R 4 , and R 5  represent each a substituent; n represents 0 or an integer of 1 to 3; m represents 0 or an integer of 1 to 6; and p represents an integer of 1 to 3; and pharmacologically acceptable salts thereof. The compound has a serotonin antagonism and is clinically useful as medicament, in particular, for treating, ameliorating and preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.

This application is a divisional of co-pending application Ser. No.09/367,227, filed on Aug. 11, 1999, for which priority is claimed under35 U.S.C. §120. application Ser. No. 09/367,227 issued as U.S. Pat. No.6,448,243 B1 on Sep. 10, 2002. application Ser. No. 09/367,227 is theU.S. national phase under 35 U.S.C. §371 of PCT InternationalApplication No. PCT/JP98/01481 filed on Mar. 31, 1998. The entirecontents of each of the above-identified applications are herebyincorporated by reference. This application also claims priority under35 U.S.C. §119 to Application No. JP 9-98433 and JP 9-366764 filed inJapan on Mar. 31, 1997 and Dec. 26, 1997, respectively.

BACKGROUND OF THE INVENTION

This invention relates to clinically useful medicaments having aserotonin antagonism, in particular for treating, ameliorating,andpreventing spastic paralysis or central muscle relaxants forameliorating myotonia.

Myotonia, which seriously restrains daily life, is induced by any of anumber of factors or a combination thereof, for example,cervico-omo-brachial syndromes accompanying stiffness or pain in theneck, shoulder, arm, lumbar, and dorsal skeletal muscles due to abnormalposture, fatigue, changes in the backbone with ageing, etc., shoulderperiarthritis accompanying inflammation in the tissues constituting theshoulder joint due to changes in the shoulder joint caused by trauma,etc., and spastic paralysis wherein accelerated limb muscle tonushinders voluntary movements.

In particular, spastic paralysis is a disease which accompanies limbmuscle tonus, stiffening, walking difficulty, etc., and thus seriouslyrestrains daily life.

It has been a practice to treat these diseases mainly with the use ofmedicaments. At the present stage, central muscle relaxants orperipheral muscle relaxants are administered to patients with thesediseases. Particular examples of such central muscle relaxants includeTolperisone hydrochloride, Baclofen, Tizanidine hydrochloride,Chlorzoxazone, and Diazepam. Particular examples of such peripheralmuscle relaxants include suxamethonium chloride, Pancuronium bromide,and dantrolene sodium.

Central muscle relaxants act selectively on the central nervous systemso as to relaxmuscles. Therefore, it is expected that those action onthe upper center would exhibit a more potent muscle relaxant effect.However, there arise at the same time some problems includingextrapyramidal symptoms and neurologic manifestations such assleepiness, sluggishness, and atony. No medicament capable of achievingwell-balanced principal action and side effects has been known hitherto.

Diazepam, which is inherently a minor tranquilizer, is efficaciousagainst diseases accompanying mental symptoms such as anxiety, tensionand depression. However, its effect is too potent to merely amelioratemyotonia. With the use of diazepam, therefore, spastic paralysis can berelieved but there arise some problems such as dizziness. Suxamethoniumchloride and Pancuronium bromide, which are peripheral muscle relaxants,are marketed exclusively as injections, which makes the chronicadministration thereof difficult. Dantrolene sodium is processed intoinjections and preparations for oral use and has a relatively potentmuscle relaxant effect. However, it has only a lowmarginof safetyandfrequently induces muscular atony. Accordingly, it is difficult forthose other than medical specialists to administer this medicine.

SUMMARY OF THE INVENTION

In view of the lack of a clinically useful, highly safe medicament fortreating and amelioriating mytonia in spastic paralysis and the like, asdiscussed above, the present inventors have developed medicaments fortreating, ameliorating, and preventing spastic paralysis or centralmuscle relaxants which have a potent effect of ameliorating myotoniawhile sustaining a high safety profile. It has been found that a novelclass of 1,4-substituted cyclic amine derivatives represented by thefollowing formula, and pharmacologically acceptable salts thereof, havean excellent central muscle relaxant effect while maintaining a highsafety safety profile. This discovery makes it possible to solve theabove problems, thus completing the present invention.

Accordingly, the present invention aims at providing clinically usefulnovel medicaments which have well-balanced principal action and sideeffects and make it possible to overcome the problem encountering in theprior art that those acting on the upper center would exhibit a morepotent muscle relaxant effect but at the same time suffer from someproblems including extrapyramidal symptoms and neurologic manifestationssuch as sleepiness, sluggishness and weakness.

Because of the anti-serotonin effect, it is expected that the1,4-substituted cyclic amine derivative (I) of the present invention ismoreover usable in preventing, treating and ameliorating depression,emotional disorders, schizophrenia, sleep disturbance, anxiety, spinalcord injury, thrombosis, hypertension, brain circulatory disturbances,peripheral circulatory disturbances, drug addiction, etc.

The 1,4-substituted cyclic amine derivative (I) according to the presentinvention is represented by the following formula:

wherein A, B, C and D are the same or different from one another andeach represents methine or nitrogen, provided at least two of them aremethine;

the bond represented by the following formula:- - - - -represents a single or double bond;

T represents methine or nitrogen;

Y and Z are the same or different from each other and each representsmethine, nitrogen, a group represented by the following formula:

or a group represented by the following formula:

provided at least one of them represents nitrogen;

R¹ and R² are the same or different from each other and each representshydrogen, halogeno, hydroxy, lower alkylsulfonylaminoalkyl, lowerhalogenated-alkylsulfonylaminoalkyl, 2-pyrrolidinon-1-yl,1-hydroxy-1-(methoxypyridyl)methyl, methoxypyridylcarbonyl,1,3-propanesultum-2-yl, lower hydroxypiperidylcarbonylalkyl, lowerhydroxyalkylamidoalkyl, lower halogenated-alkylamidoalkyl, lowerdihalogenated-alkylamidoalkyl, lower heteroarylamidoalkyl, lowerhydroxyalkylamidoalkyl, optionally substituted amino, nitro, loweralkyl, lower alkoxy, lower acyl, lower alkoxyalkoxy, cyano, loweralkylsulfonyl, sulfonylamido, hydroxy-lower alkyl, hydroxy-lower alkoxy,lower alkoxycarbonylamino, lower alkylsulfonylamino, N-loweralkylalkylsulfonylamino, lower acylamino, optionally substitutedaminoalkyl, optionally N-substituted lower acylaminoalkyl, optionallysubstituted aryl, optionally substituted arylsulfonylamino, loweralkylsulfonyloxy, hydroxyiminomethyl, (2-pyrrolidon-1-yl)methyl,(2-piperidon-1-yl)methyl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroarylalkyl,cycloalkylcarbonylaminoalkyl, optionally substituted ureido, optionallysubstituted ureido-lower alkyl, succinimido, (succinimido-1-yl)-loweralkyl, amido, optionally substituted carbamoyl, optionally substitutedcarbamoyl-lower alkyl, optionally substituted thiocarbamoyl-lower alkyl,formyl, aromatic acyl, heteroarylcarbonyl, halogenated lower alkyl,(2-imidazolidinon-1-yl)methyl, (2,4-imidazolidinedion-3-yl)methyl,(2-oxazolidon-3-yl)methyl, (glutarimido-1-yl)methyl, optionallysubstituted heteroarylhydroxyalkyl, cyano-lower alkyl, 1-hydroxy lowercycloalkyl, (2,4-thiazolidinedion-3-yl)methyl, optionally substituted4-piperidylmethyl, heteroarylacyl, pyrrolidinylcarbonyl-lower alkyl,optionally substituted aminosulfonylalkyl, carboxy-lower alkyl or loweralkylamidoalkyl; or alternatively R¹ and R² together may form optionallysubstituted alicycle, optionally substituted heterocycle oralkylenedioxy, provided these rings may be substituted;

R³ represents hydrogen, halogeno, lower alkyl, hydroxy, hydroxy-loweralkyl, lower alkoxy, formyl, optionally substituted aralkyloxy,hydroxy-lower alkoxy, optionally substituted sulfamoyl or optionallyN-substituted sulfamoyl-lower alkyl;

R⁴ represents hydrogen, lower alkyl, hydroxy-lower alkyl, loweralkoxyalkyl, optionally aryl-substituted aryloxyalkyl or optionallyaryl-substituted aralkyloxyalkyl;

R⁵ represents lower alkyl, lower acyl, lower alkoxycarbonyl, aromaticacyl or a group represented by the following formula:-Q¹-(CH₂)-Q²-R⁶[wherein

Q¹and Q² are both single bonds, or one of them is a single bond whilethe other represents oxygen, carbonyl, a group represented by —NHCO—, agroup represented by —NHSO₂— or a group represented by >CH—R⁷ (whereinR⁷ represents hydroxy, lower alkyl or halogeno):

s represents 0 or an integer of 1 to 6; and

R⁶ represents optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted benzoheteroaryl, 1,4-benzodioxanyl,1,3-benzodioxolyl, benzothiazolyl or cyano];

n represents 0 or an integer of 1 to 3;

m represents 0 or an integer of 1 to 6; and

p represents an integer of 1 to 3.

DETAILED DESCRIPTION OF THE INVENTION

The term “halogens” as used in the above definition particularly meanschloro, fluoro, bromo and iodo.

The term “optionally substituted amino” particularly means aminooptionally substituted by lower alkyl, optionally substituted aryl, etc.

The term “lower alkyl” particularly means C₁₋₆ alkyl such asmethyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl.The term “lower alkoxy” particularly means those consisting of the abovelower alkyl and oxygen bonded thereto such as methoxy, ethoxy andpropoxy. The term “lower acyl” particularly means those consisting oflower alkoxy and carbonyl bonded thereto such as acetyl, propionyl andbutyryl. The term “lower alkoxyalkoxy” particularly means the abovelower alkoxy further substituted by lower alkoxy such as methoxymethoxy,methoxyethoxy and methoxypropoxy. The term “lower alkylsulfonyl”particularly means the above lower alkyl bonded to sulfonyl (—SO₂—) suchas methanesulfonyl and ethanesulfonyl. The term “sulfonylamido” meansthose represented by the formula (—SO₂NH₂). The term “hydroxy-loweralkyl” particularly means the above lower alkyl substituted by one ormore hydroxy groups such as hydroxymethyl, hydroxyethyl andhydroxypropyl. The term “lower alkylsulfonylamino” particularly meansthe above lower alkyl bonded to sulfonylamino (—SO₂N<) such asmethanesulfonylamino, ethanesulfonylamino, propanesulfonylamino,butanesulfonylamino and N-methylmethanesulfonylamino. The term “loweracylamino” particularly means amino bonded to lower (C₂₋₆) fatty acidssuch as acetamido, propionamido and butyrylamido.

The term “optionally N-substituted lower acylaminoalkyl” particularlymeans the above lower acyl bonded to amino-lower alkyl such asacetamidomethyl, acetamidoethyl, propionamidomethyl andbutrylamidomethyl which may be further N-substituted by lower alkyl,etc.

The term “optionally substituted arylsulfonylamino” particularly meansaryl bonded to sulfonylamino (—SO₂NH—) and optionally furthersubstituted such as benzenesulfonylamino and toluenesulfonylamino. Theterm “lower alkylsulfonyloxy” particularly means the above lower alkylbonded to sulfonyloxy (—SO₃—). The term “optionally substitutedaminoalkyl” particularly means amino bonded to the above lower alkylwhich may be further N-substituted by lower alkyl, lower alkylsulfonyl,etc.

The term “optionally substituted aryl” particularly means optionallysubstituted phenyl, optionally substituted naphthyl, etc. Preferablesubstituents are a halogen or a lower alkoxy, and further preferable arefluorine, chlorine and methoxy. And plural substituents may be used,which are the same as or different from one another. The term“optionally substituted heteroaryl” particularly means optionallysubstitutedpyridyl, pyrazyl, pyrimidyl, pyrrolyl, imidazolyl, pyrazolyl,quinolyl, isoquinolyl, furyl, thienyl, thiazolyl, etc. The term“optionally substituted aralkyl” particularly means optionallysubstituted benzyl, phenethyl, phenylpropyl, etc. The term “optionallysubstituted heteroarylalkyl” particularly means optionally substitutedpyridylmethyl, pyridylethyl, pyrazylethyl, pyridonemethyl,pyrrolidonemethyl, pyrrolylmethyl, imidazolylmethyl, triazolylmethyl,thiazolylmethyl, etc. The term “cycloalkylcarbonylaminoalkyl” meanscarbonylaminoalkyl bonded to C₃₋₈ cycloalkyl.

The term “optionally substituted carbamoyl-lower alkyl” particularlymeans, for example, carbamoylmethyl (H₂NCOCH₂—) optionally N-substitutedby lower alkyl, cycloalkyl, lower hydorxyalkyl, lower dihydroxyalkyl,lower carbamoylalkylcarbamoylalkyl, lower dialkylaminoalkyl, lowercyanoalkyl, lower alkoxyalkyl, lower halogenated-alkyl, etc. at the 1 or2 position. The term “optionally substituted thiocarbamoyl-lower alkyl”particularly means, for example, thiocarbamoylmethyl (H₂NCSCH₂—)optionally N-substituted by lower alkyl, etc.

The term “heteroarylcarbonyl” particularly means pyridylcarbonyl,pyrrolylcarbonyl, thaizolylcarbonyl, etc. The term “halogenated loweralkyl” means lower alkyl substituted with halogeno such as chloromethyl,fluoromethyl, fluoroethyl, etc.

The term “optionally substituted heteroarylhydroxyalkyl” particularlymeans pyridylhydroxymethyl, thiazolylhydroxymethyl,pyrimidylhydroxymethyl, pyrrolylhydroxymethyl, etc.

More particularly, the 1,4-substituted cyclic amine derivatives (I) ofthe present invention are exemplified by the following compounds, thoughthe present invention is not restricted thereto:

(1) 1-[1-(4-fluorophenyl)piperidin-4-yl]indoline,

(2) 1-[1-(4-fluorobenzyl)piperidin-4-yl]indoline,

(3) 1-(1-phenethylpiperidin-4-yl)indoline,

(4) 1-[1-(4-bromophenethyl)piperidin-4-yl]indoline,

(5) 1-[1-(3-chlorophenethyl)piperidin-4-yl]indoline,

(6) 1-[1-(4-chlorophenethyl)piperidin-4-yl]indoline,

(7) 1-[1-(2-fluorophenethyl)piperidin-4-yl]indoline,

(8) 1-[1-(3-fluorophenethyl)piperidin-4-yl]indoline,

(9) 1-[1-(4-fluorophenethyl)piperidin-4-yl]indoline,

(10) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]indoline,

(11) 1-[1-(3,4-difluorophenethyl)piperidin-4-yl]indoline,

(12) 1-[1-(3,5-difluorophenethyl)piperidin-4-yl]indoline,

(13) 1-[1-(4-fluorophenylpropyl)piperidin-4-yl]indoline,

(14) 1-{1-[2-(4-fluorophenyl)propyl]piperidin-4-yl}indoline,

(15) 1-[1-(4-fluorophenylbutyl)piperidin-4-yl]indoline,

(16) 1-[1-(4-fluorophenethyl)piperidin-4-yl]methylindoline,

(17) 1-{2-[1-(4-fluorophenethyl)piperidin-4-yl]ethyl}indoline,

(18) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]indoline,

(19) 1-[1-(3-methoxyphenethyl)piperidin-4-yl]indoline,

(20) 1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline,

(21) 1-[1-(4-cyanophenethyl)piperidin-4-yl]indoline,

(22) 1-[1-(3-hydroxymethylphenethyl)piperidin-4-yl]indoline,

(23) 1-[1-(4-hydroxymethylphenethyl)piperidin-4-yl]indoline,

(24) 1-{1-[4-(2-hydroxyethyl)phenethyl]piperidin-4-yl}indoline,

1-{1-[14-(1-hydroxyethyl)phenethyl]piperidin-4-yl}indoline,

(26) 1-{1-[4-(2-hydroxyethoxy)phenethyl]piperidin-4-yl}indoline,

(27) 1-[1-(4-trifluoromethylphenethyl)piperidin-4-yl]indoline,

(28) 1-[1-(4-methanesulfonylphenethyl)piperidin-4-yl]indoline,

(29) 1-[1-(4-nitrophenethyl)piperidin-4-yl]indoline,

(30) 1-[1-(4-aminophenethyl)piperidin-4-yl]indoline,

(31) 1-[1-(4-methylsulfonylaminophenethyl)piperidin-4-yl]indoline and1-{1-[4-bis(methylsulfonyl)aminophenethyl]piperidin-4-yl}indoline,

(32) 1-[1-(4-acetamidophenethyl)piperidin-4-yl]indoline,

(33) 1-[1-(4-ethylaminophenethyl)piperidin-4-yl]indoline,

(34) 1-[1-(4-hydroxyiminomethylphenethyl)piperidin-4-yl]indoline,

(35) 1-[1-(4-aminomethylphenethyl)piperidin-4-yl]indoline,

(36) 1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indoline,

(37) 1-[1-(4-chloroacetamidomethylphenethyl)piperidin-4-yl]indoline,

(38)1-[1-(4-methanesulfonylaminomethylphenethyl)-piperidin-4-yl]indoline,

(39)1-[1-(4-propionylaminomethylphenethyl)piperidin-4-yl]-3-methylindoline,

(40) 1-[1-(4-carbamoylphenethyl)piperidin-4-yl]indoline,

(41) 1-[1-(4-N-isopropylcarbamoylmethylphenethyl)piperidin-4-yl]indoline,

(42) 1-[1-(4-sulfamoylphenethyl)piperidin-4-yl]indoline,

1-{1-[2-hydroxyethoxy)phenethyl]piperidin-4-y1}indoline,

(44) 1-{1-[4-(2-dimethylaminoethoxy)phenethyl]piperidin-4-yl}indoline,

(45) 1-{1-[3,4-di(hydroxymethyl)phenethyl]piperidin-4-yl}indoline,

(46) 1-{1-[3,4-(methylenedioxy)phenethyl]piperidin-4-yl}indoline,

(47)1-{1-[2-(4-chlorophenylsulfonylamino)ethyl]-piperidin-4-yl}indoline,

(48)1-{1-[2-(4-methoxyphenylsulfonylamino)ethyl]-piperidin-4-yl}indoline,

(49) 1-{1-[2-(4-pyridyl)ethyl]piperidin-4-yl}indoline,

(50) 1-{1-[2-(2-pyridyl)ethyl]piperidin-4-yl}indoline,

(51) 1-{1-[2-(3-pyridyl)ethyl]piperidin-4-yl}indoline,

(52) 1-{1-[2-(2-methoxy-5-pyridyl)ethyl]piperidin-4-yl}indoline,

(53) 1-{1-[2-(3-methoxypyridin-5-yl)ethyl]piperidin-4-yl}indoline,

(54) 1-{1-[2-(2-cyanopyridin-5-yl)ethyl]piperidin-4-yl}indoline,

(55)1-{1-[2-(2-hydroxymethylpyridin-5-yl)ethyl]-piperidin-4-yl}indoline,

(56)1-{1-[2-(3-hydroxymethylpyridin-5-yl)ethyl]-piperidin-4-yl}indoline,

(57) 1-[1-(2,6-difluoro-3-pyridylethyl)piperidin-4-yl]indoline,

(58) 1-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}indoline,

(59) 1-{1-[2-(3-thienyl)ethyl]piperidin-4-yl}indoline,

(60) 1-[1-(2-thiazolylethyl)piperidin-4-yl]indoline,

(61) 1-[1-(4-methyl-5-thiazolylethyl)piperidin-4-yl]indoline,

(62) 1-{1-[(indol-3-yl)ethyl]piperidin-4-yl}indoline,

(63) 1-{1-[2-(6-benzothiazolyl)ethyl]piperidin-4-yl}indoline,

(64) 1-[1-(5-methoxy-2-thienyl)ethylpiperidin-4-yl]indoline,

(65) 1-[1-(2-methoxy-5-thiazolyl)ethylpiperidin-4-yl]indoline,

(66) 1-[1-(2-cyano-5-thiazolyl)ethylpiperidin-4-yl]indoline,

(67) 1-(1-pyrazinylethylpiperidin-4-yl)indoline,

(68) 1-{1-[2-(4-bromopyrazol-1-yl)ethyl]piperidin-4-yl}indoline,

(69) 1-{1-[3-(4-fluorophenoxy)propyl]piperidin-4-yl}indoline,

(70) 1-{1-[3-(4-hydroxymethylphenoxy)propyl]piperidin-4-yl}indoline,

(71) 1-{1-[3-(4-hydroxyethylphenoxy)propyl]piperidin-4-yl}indoline,

(72) 1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}indoline,

(73) 1-{1-[4-(4-fluorophenyl)-4-hydroxybutyl]piperidin-4-yl}indoline,

(74) 1-[1-(phthalimido-1-yl)ethylpiperidin-4-yl]indoline,

(75) 1-[1-(4-fluorobenzamido)ethylpiperidin-4-yl]indoline,

(76) 1-{1-[1-(3,4-dimethoxyphenyl)propan-2-yl]piperidin-4-yl}indoline,

(77) 1-{1-[(1,4-benzodioxan-2-yl)methyl]piperidin-4-yl}indoline,

(78) 1-{1-[3-(3,4-methylenedioxyphenoxy)propyl]piperidin-4-yl}indoline,

(79) 1-[1-(4-fluorophenethyl)-3-methylpiperidin-4-yl]indoline,

(80) 1-(1-benzyl-3-hydroxymethylpiperidin-4-yl)indoline,

(81) 1-[1-(4-fluorophenethyl)-3-hydroxymethylpiperidin-4-yl]indoline,

(82) 1-[1-(4-fluorophenethyl)-3-hydroxymethylpiperidin-4-yl]indoline,

(83)1-[2-(4-acetamidomethylphenyl)ethyl]-4-(indan-1-yl)piperidin-1-oxide,

(84) 1-[1-ethyl-3-(4-fluorophenoxymethyl)piperidin-4-yl]indoline,

(85) 1-[1-ethyl-3-(4-fluorobenzyloxymethyl)piperidin-4-yl]indoline,

(86) 1-[1-ethyl-3-(4-fluorobenzyloxymethyl)piperidin-4-yl]indoline,

(87) 1-(1-acetylpiperidin -4-yl) indoline -7-carbaldehyde,

1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-bromoindoline,

1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-hydroxymethylindoline,

1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-aminomethylindoline,

(91) 1-(1-benzylpiperidin-4-yl)-6-bromoindoline,

(92) 1-(1-benzylpiperidin-4-yl)-6-fluoroindoline,

(93) 1-(1-benzylpiperidin-4-yl)-6-formyindoline,

(94) 1-(1-benzylpiperidin-4-yl)-6-hydroxyiminomethylindoline,

(95) 1-(1-benzylpiperidin-4-yl)-6-aminomethylindoline,

(96) 1-(1-benzylpiperidin-4-yl)-6-acetamidomethylindoline,

(97) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-acetamidomethylindoline,

(98) 1-[1-(4-chlorophenethyl)piperidin-4-yl]-6-acetamidornethylindoline,

(99) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-5-methoxyindolime,

(100) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromnoindoline,

(101) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline,

(102) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloroindoline,

(103) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoroindoline,

(104) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyindoline,

(105) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-4-methoxyindolime,

(106) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline,

(107) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-methoxyindoline,

(108) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6,7-dimethoxyindoline,

(109) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-nitroindoline,

(110) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminoindoline:

(111) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methylaminoindoline,

(112) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ethylaminoindoline,

(113) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isopropylaminoindoline,

(114) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-dimethylaminoindoline,

(115) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoindoline,

(116)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonylaminoindoline,

(117)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ethanesulfonylaminoindoline,

(118)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-propanesulfonylaminoindoline,

(119)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-fluorobenzenesulfonylamino)indoline,

(120)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylmethanesulfonylamino)indoline,

(121) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyethoxyindoline,

(122)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonyloxyindoline,

(123) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-hydroxyethoxyindoline,

(124) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanoindoline,

(125) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylindoline,

(126)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-pyrrolylcarbonyl)indoline,

(127) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetylindoline,

(128) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonylindoline,

(129)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-thiocarbamoylmethylindoline,

(130) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline,

(131)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindoline,

(132) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline,

(133) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,

(134) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,

(135) 1-[1-(3-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,

(136) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline,

(137)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyethyl)indoline,

(138)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxypropyl)indoline,

(139)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-1-methylethyl)indoline,

(140)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxycyclobutyl)indoline,

(141)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxycyclopentyl)indoline,

(142) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline,

(143) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoromethylindoline,

(144) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-fluoroethyl)indoline,

(145) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanomethylindoline,

(146) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline,

(147) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindoline,

(148)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(methylcarbamoylmethyl)indoline,

(149)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(ethylcarbamoylmethyl)indoline,

(150)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-propylcarbamoylmethyl)indoline,

(151)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(isopropylcarbamoylmethyl)indoline,

(152)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(isobutylcarbamoylmethyl)indoline,

(153)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(t-butylcarbamoylmethyl)indoline,

(154)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(cyclopropylcarbamoylmethyl)indoline,

(155)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(tetramethylenecarbamoylmethyl)indoline,

(156)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-propionylaminomethylindoline,

(157)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-butyryl)aminomethylindoline,

(158)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isobutyrylaminomethylindoline,

(159)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyclopropanecarboxamidomethylindoline,

(160)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methylsulfonylaminomethylindoline,

(161) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ureidomethylindoline,

(162)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylaminomethylindoline,

(163)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylacetamidomethylindoline,

(164)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylsulfamoylmethyl)indoline,

(165)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-acetamidoethyl)indoline,

(166) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoethylindoline,

(167)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(piperidin-4-yl)methyl]indoline,

(168)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(1-acetylpiperidin-4-yl)methyl]indoline,

(169)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(1-ethylpiperidin-4-yl)methyl]indoline,

(170)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(1-methylpiperidin-4-yl)methyl]indoline,

(171) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyridyl)indoline,

(172) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-thiazolyl)indoline,

(173)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-methylpyrrol-2-yl)indoline,

(174)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)methyl]indoline,

(175)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(2-pyridyl)methyl]indoline,

(176)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(3-pyridyl)methyl]indoline,

(177)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(3-pyridyl)methyl]indoline,

(178)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-4-pyridylmethyl)indoline,

(179)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-pyridylmethyl)indoline,

(180)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyridylcarbonyl)indoline,

(181)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)ethyl]indoline,

(182)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[l-(2-pyridyl)ethyl]indoline,

(183)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-pyridylcarbonyl)indoline,

(185)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(2-methoxypyridin-3-yl)methyl]indoline,

(186)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-6-yl)methyl]indoline,

(187)1-[1-(4-fluorophenethyl)piperidin-4-yl)-6-[1-(2-methoxypyridin-6-yl)methyl]indoline,

(188)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-5-yl)methyl]indoline,

(189)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[l-(2-methoxypyridin-5-yl)methyl]indoline,

(190)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridon-5-yl)methyl]indoline,

(191)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-dimethylaminopyridin-5-yl)methyl]indoline,

(192)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-chloropyridin-5-yl)methyl]indoline,

(193)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(2-thiazolyl)-1-hydroxymethyl]indoline,

(194)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-thiazolylcarbonyl)indoline,

(195)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(4-thiazolyl)-1-hydroxymethyl]indoline,

(196)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(5-thiazolyl)-1-hydroxymethyl)indoline,

(197)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(pyrimidin-2-yl)methyl]indoline,

(198)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[₁-hydroxy-1-(pyrimidin-5-yl)methyl]indoline,

(199)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyrrolyl)methyl]indoline,

(200)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N,N-dimethylaminomethylindoline,

(201)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-fluorophenyl)indoline,

(202)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyrrolidon-1-yl)methylindoline,

(203)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-piperidon-1-yl)methylindoline,

(204)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(succinimido-1-yl)methylindoline,

(205)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(glutarimido-1-yl)methylindoline,

(206)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-imidazolidonyl)methylindoline,

(207)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2,4-imidazolidinedion-3-yl)methylindoline,

(208)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-oxazolidon-3-yl)methylindoline,

(209)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2,4-thiazolidinedion-3-yl)methylindoline,

(210)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(pyrrol-1-yl)methylindoline,

(211)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(imidazol-1-yl)methylindoline,

(212)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2,3-triazol-1-yl)methylindolineand

1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2,3-triazol-2-yl)methylindoline,

(213)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2,4-triazol-2-yl)methylindoline,

(214)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-thiazolyl)methylindoline,

(215)1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-(4-methoxybenzyl)indoline,

(216) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-methylindoline,

(217) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-5-chloro-6-aminoindoline,

(218)1-[1-(4-fluorophenethyl)piperidin-4-yl]-5-chloro-6-methanesulfonylaminoindoline,

(219)1-[1-(4-fluorophenethyl)piperidin-4-yl]-5-chloro-6-methoxyindoline,

(220) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-aminoindoline,

(221)1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-methanesulfonylaminoindoline,

(222) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-acetamidoindoline,

(223) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-bromoindoline,

(224)1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,

(225)1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindoline,

(226)1-{1-[3-(4-fluorophenyl)propyl]piperidin-4-yl}-6-acetamidomethylindoline,

(227)1-{1-[4-(4-fluorophenyl)butyl]piperidin-4-yl}-6-acetamidomethylindoline,

(228) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-methoxyindoline,

(229) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-fluoroindoline,

(230) 1-[1-(4-sulfamoylphenethyl)piperidin-4-yl]-6-methoxyindoline,

(231) 1-[1-(4-fluorophenoxypropyl)piperidin-4-yl]-6-bromoindoline,

(232)1-[1-(4-fluorophenoxypropyl)piperidin-4-yl]-6-acetamidomethylindoline,

(233) 1-{1-[2-(6-benzothiazolyl)ethyl]piperidin-4-yl}-6-methoxyindoline,

(234) 1-{1-(4-fluorophenethyl)piperidin-4-yl}thiazolo[5,4-]indoline,

(235)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminothiazolo[5,4-f]indoline,

(236)1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-hydroxy-(4a,7a)-cyclohexanoindolineand

1-[1-(4-fluorophenethyl)piperidin-4-yl]-4-hydroxy-(3b,6a)-cyclohexanoindoline,

(237)1-(1-methylpiperidin-4-yl)-6-(4-fluorobenzene-sulfonylamino)indoline,

(238)1-(1-ethylpiperidin-4-yl)-6-(4-fluorobenzene-sulfonylamino)indoline,

(239) 1-(1-ethylpiperidinyl)-4-(4-fluorophenyl)indoline,

(240) 1-(1-ethylpiperidin-4-yl)-3-(4-fluorophenyl)-indoline,

(241) 1-(1-ethylpiperidin-4-yl)-3-(4-methoxyphenyl)-indoline,

(242) 1-(1-ethylpiperidin-4-yl)-3-(4-methoxybenzyl)-indoline,

(243) 1-[(1-ethylpiperidin-4-yl)methyl]-3-(4-methoxy-benzyl)indoline,

(244) 1-(1-ethylpiperidin-4-yl)-3-(4-fluorobenzyl)-indoline,

(245) 1-(1-ethylpiperidin-4-yl)-3-(3-pyridylmethyl)-indoline,

(246) 1-(1-ethylpiperidin-4-yl)-3-(3-methoxyphenethyl)-indoline,

(247) 1-(1-ethylpiperidin-4-yl)-3-(3-fluorophenethyl)-indoline,

(248) 1-[1-(4-fluorophenethyl)piperidin-4-yl]indan,

(249) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]indan,

(250) 1-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-6-methoxyindan,

(251) 1-(4-ethylpiperazin-1-yl)-6-methoxyindan,

(252) 1-(4-ethylpiperazin-1-yl)-2-ethoxycarboxyaminoindan,

(253) 1-(4-ethylpiperazin-1-yl)-2-methylaminoindan,

(254)1-(4-ethylpiperazin-1-yl)-2-[methyl-(4-trifluorobenzyl)amino]indan,

(255)7-[4-hydroxy-1-(4-fluorophenethyl)piperidin-4-yl]-5,6-dihydro-7H-pyrindine,

(256) 7-[1-(4-fluorophenethyl)piperidin-4-ylidene]-5,6-dihydropyrindine,

(2 57) 7-[1-(4-fluorophenethyl)piperidin-4-yl]-5,6-dihydro-7H-pyrindine,

(258) 7-[4-(4-fluorophenethyl)piperazin-1-yl]-5,6-dihydro-7H-pyrindine,

(259) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloro-7-azaindoline,

(260) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-azaindoline,

(261) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoro-7-azaindoline,

(262)1-(1-(2,4-difluorophenethyl)piperidin-4-yl]-6-chloro-7-azaindoline,

(263) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-chloro-7-azaindoline,

(264) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-azaindoline,

(265)5-[1-(4-fluorophenethyl)piperidin-4-ylidene]-7-methyl-5,6-dihydrocyclopentapyrazine,

(266)5-[1-(4-fluorophenethyl)piperidin-4-yl]-7-methyl-5,6-dihydro-5H-cyclopentapyrazine,

(267)1-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,

(268) 1-{1-[2-(4-fluorophenyl) ethyl piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,

(269)1-[1-(4-cyanopropyl)piperidin-4-yl]-7-methoxy-1,2,3,4-tetrahydroquinoline,

(270)1-{1-[2-(2-thienyl)ethyl]lpiperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,

(271)1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7,8-dimethoxy-1,2,3,4-tetrahydroquinoline,

(272)1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7,8-methylenedioxy-1,2,3,4-tetrahydroquinoline,

(267)1-{-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7-methoxy-8-methyl-1,2,3,4-tetrahydroquinoline,

(274)1-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,

(275)1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,

(276)1-{l-[2-(4-fluorophenyl)-2-fluoroethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,

(277)1-[2-(4-fluorophenyl)ethyl]-4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine,

(278)1-[2-(4-fluorophenyl)ethyl]-4-[6-(2-hydroxy)ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]piperidine,

(279)trans-1-(4-ethylpiperazin-1-yl)-7-methoxy-2-(4-trifluoromethylphenoxy)-1,2,3,4-tetrahydronaphthalene,

(280)1-{4-[2-(4-f1uoropheny1)ethyl]piperazin-1-yl}-7-methoxy-1,2,3,4-tetrahydronaphthalene,

(281)1-{4-[2-(4-fluorophenyl)-2-oxoethyl]piperazin-1-yl}-7-methoxy-1,2,3,4-tetrahydronaphthalene,

(282)1-(4-fluorophenethyl)-4-(2-methoxybenzocycloheptan-9-yl)piperazine,

(283)5-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydroisoquinoline,

(284)1-[1-(4-fluorophenethyl)piperidin-4-yl]-5,6-methylenedioxyindoline,

(285) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,

(286)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-isopropylcarbamoylmethyl)indole,

(287)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-methylpyrrol-2-yl)indole,

(288) 1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indole,

(289) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanoindole,

(290) 1-[1-(4-fluorophenethyl)-3-methylpiperidin-4-yl]indole,

(291) 1-[1-(4-fluorophenethyl)homopiperidin-4-yl]-6-methoxyindoline,

(292) 1-[1-(4-fluorophenethyl)pyrrolidin-3-yl]-6-methoxyindoline,

(293) 3,3-dimethyl-1-[1-(4-fluorophene thyl) piperidin-4-yl]-6-bromoindoline,

(294)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(ethylcarbamoylmethyl)indoline,

(295)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[N-(cyclopropylcarbamoyl)methyl]indole,

(296)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[N-(isobutylcarbamoyl)methyl]indole,

(297 )1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-propylcarbamoylmethy)indoline,

(298)1-[-(4-fluorophenethyl)piperidin-4-yl]-6-(tetramethylenecarbamoylmethyl)indole,

(299)1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindole,

(300)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-hydroxyethyl)carbamoylmethylindole,

(301)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-dimethylcarbamoylmethylindole,

(302)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-hydroxypiperidin-1-yl)carbonylmethylindole,

(303)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[bis(2-hydroxyethyl)carbamoylmethyl]indole,

(304)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,3-dihydroxypropan-2-yl)carbamoylmethylindole,

(305) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbaoylmethylindole,

(306) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(carbamoylmethyl)carbaoylmethylindole,

(307)1-(1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-dimnethylamninoethyl)carbarnoylmnethylindole,

(308)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanormethylcarbaoylrmethylindolei,

(309)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-methoxyethyl)lcarbarboylmethylindole,

(310)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-fluoroethyl)carbamoylmethylindole,

(311)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(ethylcarbamoyl)ethyl]indole,

(312)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(pyrrolidin-1-yl)ethyl]carbamoylmethylindole,

(313)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(morpholin-4-yl)ethyl]carbamoylmethylindole,

(314)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(pyridin-4-yl)methylcarbamoylmethylindole,

(315)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(pyridin-2-yl)ethyl]carbamoylmethylindole,

(316)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethylindole,

(317)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-methoxypyridin-5-yl)carbonylindole,

(318)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(2-methoxypyridin-5-yl)hydroxymethyl]indole,

(319) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyproyl)indole,

(320)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-1-methylethyl)indoline,

(321) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-hydroxypropyl)indole,

(322)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonamidomethylindole,

(323)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isopropylsulfonamidomethylindole,

(324)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-n-propylsulfonamidomethylindole,

(325)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-chloropropyl)sulfonamidomethylindole,

(326)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,3-propanesultam-2-yl)methylindole,

(327)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-propionylaminomethylindole,

(328)3-chloro-1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-acetamidomethylindole,

(329)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-hydroxybutyroylamidomethyl)indole,

(330) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyethoxyindole,

(331) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonylindole,

(332) 1-[1-(2,6-difluoro-3-pyridylethyl)piperidin-4-yl]indole,

(333) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoroindole,

(334) 1-[1-(4-fluorophenethyl)piperidin-4-yl]thiazolo-[5,4-f]indole,

(335)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylmethanesulfonylamino)indole,

(336)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonyloxyindole,

(337) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylindole,

(338)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylsulfamoylmethyl)indole,

(339) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoindole,

(340)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2-dihydroxypropan-3-yl)carbamoylmethylindole,

(341)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(pyridin-2-yl)methylcarbamoylmethylindole,

(342)1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethylindole,

(343)1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(1-acetylpiperidin-4-yl)methylcarbamoylmethylindole,

(344)1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-ethylcarbamoylmethylindole,

(345)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-ethylpiperidin-4-yl)methylcarbamoylmethylindole,

(346)1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(2-hydroxyethyl)carbamoylmethylindole,

(347) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,3-dioxolan-2-yl)methylcarbamoylmethylindole,

(348) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole,

(349) 1-[1-(4-chlorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,

(350) 1-[1-(3-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,

(351) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-acetamnidomethylindoie,

(352) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,

(353)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2,4-imidazolidinedion-3-yl)methylindole,

(354)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isobutyrylaminomethylindole,

(355)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-imidazolidonyl)methylindole,

(356)1-{1-[4-(4-fluorophenyl)butyllpiperidin-4-yl}-6-acetamidomethylindole,

(357)1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,

(358)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyrrolidon-1-yl)methylindole,

(359)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylacetamidomethylindole,

(360)1-{1-[3-(4-fluorophenyl)propyl]piperidin-4-yl}-6-acetamidomethylindole,

(361)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylaminomethylindole,

(362)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-butyryl)aminomethylindole,

(363)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyclopropanecarboxamidomethylindole,

(364)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyacetamidomethylindole,

(365)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoroacetamidomethylindole,

(366)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-fluoroacetamidomethylindole,

(367)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-chloropropionylamino)methylindole,

(368)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-imidazocarbonylaminomethylindole,

(369)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-hydroxypropionylamino)methylindole,

(370)1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-formyl-6-acetamidomethylindole,

(371)1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-hydroxyimino-6-acetamidomethylindole,.

(372)1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-hydroxymethyl-6-acetamidomethylindole,

(373)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloroacetamidomethylindole,

(374)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoacetamidomethylindole,

(375)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N,N-dimethylaminoacetamido)methylindole,

(376)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(piperidin-1-yl)acetamido]methylindole,

(377)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-bromopropionylamino)methylindole,

(378)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-N,N-dimethylarninopropionyl)aminomethylindole,

(379)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[3-(piperidin-1-yl)propionylamino]methylindole,

(380)1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-propionylaminomethylindole,

(381)1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-fluoroacetamidomethylindole,

(382)1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(3-hydroxypropionylamino)methylindole,

(383)1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxyacetamidomethylindole,

(384)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxycarbonylaminomethylindole,

(385)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N,N-dimethylaminocarbonylaminomethylindole,

(386) 1-{1-[2-(3-pyridyl)ethyl]piperidin-4-yl}-6-acetamidomethylindole,

(387)3-cyano-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,

(388)1-{4-[(1-hydroxyethyl)phenethyl]piperidin-4-yl}-6-acetamidomethylindole,

(389) 1-[1-(4-bromophenethyl)piperidin-4-yl]-6-acetamidomethylindole,

(390) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-formylindole,

(391) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindole,

(392) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyethyl)indole,

(393) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ureidomethylindole,

(394)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-methylureido)methylindole,

(395)3,3-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoindoline,

(396)2,2-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindolineand

(397)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-methylureido)methylindole.

Although some of the 1,4-substituted cyclic amine derivatives (I) of thepresent invention occur as optical isomers or geometrical isomers,either one of these optical isomers or a mixture thereof may be used inthe present invention without restriction. Similarly, either one ofgeometrical isomers or a mixture thereof may be employed herein withoutany restriction. In the case of polymorphic crystals, either one of thecrystal forms or a mixture thereof may be used in the present inventionwithout restriction, too. Moreover, use may be made of both anhydridesand hydrates.

The pharmacologically acceptable salts to be used in the presentinvention may be arbitrary salts of the 1,4-substituted cyclic aminederivatives (I) of the present invention without particular restriction.Examples thereof include inorganic acid addition salts such ashydrochlorides, sulfates, nitrates, hydrobromides, hydriodides,perchlorates and phosphates, organic acid addition salts such asoxalates, maleates, fumarates and succinates, sulfonic acid additionsalts such as methanesulfonates, ethanesulfonates, benzenesulfonates,p-toluenesulfonates and camphorsulfonates, and amino acid additionsalts. Among all, it is preferable to use hydrochlorides and oxalatesthereof.

The 1,4-substituted cyclic amine derivative (II) according to thepresent invention is represented by the following formula:

R represents a substituent selected from among the following ones:

(wherein the bond represented by the following formula:- - - - -and R¹, R² and R³ are each as defined above); and R⁴, R⁵, Y, Z, m and pare each as defined above.

Examples of the 1,4-substituted cyclic amine derivatives (II) includecompounds similar to those cited above as the examples of the1,4-substituted cyclic amine derivatives (I), though the presentinvention is not restricted thereto.

The 1,4-substituted cyclic amine derivative (III) according to thepresent invention is represented by the following formula:

wherein the bond represented by the following formula:- - - - -and R¹, R², R³, R⁴ and R⁵ are each as defined above.

Further, the 1,4-substituted cyclic amine derivative (IV) of the presentinvention is represented by the following formula:

wherein the bond represented by the following formula:- - - - -and R¹, R², R³, R⁴, R⁶, Q¹, Q² and s are each as defined above.

Next, the 1,4-substituted cyclic amine derivative (V) according to thepresent invention is represented by the following formula:

wherein R¹, R², R³, R⁴, R⁶ and s are each as defined above.

Finally, the 1,4-substituted cyclic amine derivative (VI) according tothe present invention is represented by the following formula:

wherein R¹, R², R³, R⁴, R⁶ and s are each as defined above.

Among the 1,4-substituted cyclic amine derivatives (I) to (VI) accordingto the present invention, those which are particularly preferable fromthe viewpoint of pharmacological effects or safety are, for example, thefollowing ones:

(1) 1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indoline,

(2) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylindoline,

(3) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonylindoline,

(4) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,

(5) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyethyl)indoline,

(6)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-propylcarbamoylmethyl)indoline,

(7)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(isopropylcarbamoylmethyl)indoline,

(8) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ureidomethylindoline,

(9)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylacetamidomethylindoline,

(10)1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(4-thiazolyl)-1-hydroxymethyl]indoline,and

(11) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole.

The compounds of the present invention are each a highly safe one havingan extremely high LD₅₀.

Although compounds having the indoline or indan skeleton are disclosedin WO96/23784, JP-A 8-512,299 (WO95/01976), WO97/06155, etc., thesecompounds are completely different in structure from the 1,4-substitutedcyclic amine derivatives (I) to (VI) of the present invention.

The present invention provides the method for treating the disease whichserotonin antagonism is efficacious, by administering the effective doseof the compound as set forth or pharmacologically acceptable saltsthereof to a person, and the use of the compound as set forth orpharmacologically acceptable salts thereof for treating the diseasewhich serotonin antagonism is efficacious.

The present invention includes the following mode:

(1) 1,4-Substituted cyclic amine derivatives, which the bond representedby the following formula in the formula (I):- - - - -is a single bond, represented by the formula (XXI):

or pharmacologically acceptable salts thereof.

(2) 1,4-Substituted cyclic amine derivatives, which m is 0 in theformula (I), represented by the formula (XXII):

or pharmacologically acceptable salts thereof.

(3) 1,4-Substituted cyclic amine derivatives represented by the formula(I), in which m is 1 to 6 selected from the following compounds:

-   -   (16) 1-[1-(4-fluorophenethyl)piperidin-4-yl]methylindoline,    -   (17) 1-{2-[1-(4-fluorophenethyl)piperidin-4-yl]ethyl}indoline,        and    -   (243)        1-[(1-ethylpiperidin-4-yl)methyl]-3-(4-methoxybenzyl)indoline        or pharmacologically acceptable salts thereof.

(4) 1,4-Substituted cyclic amine derivatives represented by the formula(XXIII):

selected from the following compounds:

-   -   (256)        7-[1-(4-fluorophenethyl)piperidin-4-ylidene]-5,6-dihydropyrindine        and    -   (265)        5-[1-(4-fluorophenethyl)piperidin-4-ylidene]-7-methyl-5,6-dihydrocyclopentapyrazine        or pharmacologically acceptable salts thereof.

(5) 1,4-Substituted cyclic amine derivatives, which the bond representedby the following formula in the formula (I)- - - - -is a double bond, represented by the formula (XXIV):

or pharmacologically acceptable salts thereof.

The 1,4-substituted cyclic amine derivatives (I) of the presentinvention can be produced by, for example, the following processes,though the present invention is not restricted thereto.

(1) The case where T=N, m=0, Y=methine, and Z=N

In this case, the aimed compounds can be synthesized in accordance withthe conventional method of reductive amination, for example, the onedescribed in “Shin Jikken Kagaku Koza 14-III”, p. 1380 (Maruzen Co.,Ltd.), by reacting a fused cyclic amine (VII) with a cyclic ketone(VIII) in the presence of a reducing agent to thereby give a1,4-substituted cyclic amine derivative (IX), removing the protectinggroup theretrom if necessary, and then introducing a substituent R⁵thereinto. This reaction is represented by the following chemicalreaction formula:

[wherein the bond represented by the following formula:- - - - -represents a single or double bond;A, B, C, D, R¹, R², R³, R⁴, R⁵, n and p are each as definedabove; Pr.Grepresents hydrogen or a protecting group; and L represents a leavinggroup such as hydroxy, halogeno or methanesulfonyloxy].

It is also possible to chemically modify the substituents R¹, R², R³ andR⁴ to thereby synthesize analogs of the 1,4-substituted cyclic aminederivatives.

The reducing agent to be used herein may be an arbitrary one, so long asit is one commonly employed in reductive N-alkylation. Preferableexamples thereof include sodium triacetoxyborohydride, sodiumcyanoborohydride and lithium aluminum hydride.

(2) The case where T=N, n=0, m=0, Y=methine, and Z=N

An alternative method of (1) for synthesizing, in particular, the1,4-substituted cyclic amine derivatives (I) wherein n=0 comprisestreating the amine (XI) successively with oxalyl chloride and aluminumchloride to thereby give a diketone (XII), reducing the same to therebygive an indole derivative (XIII), removing the protecting grouptherefrom if necessary, then introducing a substituent R⁵ thereinto tothereby give an indole derivative (XIV), and reducing the same tothereby give an indoline derivative (XV). This reaction is representedby the following chemical reaction formula:

[wherein the bond represented by the following formula:- - - - -and A, B, C, D, R¹, R², R⁴, R⁵, p, Pr.G and L are each as definedabove.](1) The case of indole derivatives wherein T=N, n=0, m=0, Y=methine, andZ=N

The indole derivatives (XIV) can be obtained not only by the abovemethod (2) but also by oxidizing the indoline derivatives (XV) in aconventional manner. Although the reagent and catalyst to be used insuch a case are not particularly restricted, it is preferable to useactivated manganese dioxide.

(4) The case where T=mehtine, n=0, m=0, Y=methine, and Z=N

The aimed compounds can be synthesized by introducing a substituent R⁵into 1-(piperidin-4-yl) indan derivatives (XVI). This reaction isrepresented by the following chemical reaction formula:

[wherein the bond represented by the following formula:- - - - -and A, B, C, D, R¹, R², R⁴, R⁵, p and L are each as defined above.](5) The case where T=N, n=1, m=0,Y=methine, and Z=N

The aimed compounds can be synthesized by introducing a substituent R⁵into 1-(4-piperidinyl)-1,2,3,4-tetrahydroquinoline derivatives (XVIII)This reaction is represented by the following chemical reaction formula:

[wherein the bond represented by the following formula:- - - - -and A, B, C, D, R¹, R², R³, R⁴, R⁵, p and L are each as defined above.]

Among the 1,4-substituted cyclic amine derivatives (I) according to thepresent invention, compounds having structures other than those asdefined in the above cases (1) to (5) can be produced by the samemethods as the ones as will be described in Examples hereinafter.

To produce the 1,4-substituted cyclic amine derivatives (I) of thepresent invention, 4-substituted cyclic amine derivatives (XX)represented by the following formula are novel compounds which areuseful as intermediates in the production of the 1,4-substituted cyclicamine derivatives (I) to (VI) having a serotonin antagonism and beingclinically useful as medicaments for, in particular, treating,ameliorating and preventing spastic paralysis or central musclerelaxants for ameliorating myotonia:

wherein the bond represented by the following formula:- - - - -and A, B, C, D, R¹, R² , R³ , R⁴, n and p are each as defined above,provided that the case where R¹, R², R³ and R⁴ are all hydrogen isexcluded.

More particularly speaking, the 4-substituted cyclic amine derivatives(XX) are exemplified by the following compounds, though the presentinvention is not restricted thereto:

(1) 1-(piperidin-4-yl)-6-fluoroindoline,

(2) 1-(piperidin-4-yl)-6-bromoindoline,

(3) 1-(piperidin-4-yl)-6-nitroindoline,

(4) 1-(piperidin-4-yl)-6-methoxyindoline,

(5) 1-(piperidin-4-yl)-6-acetamidomethylindoline,

(6) 1-(piperidin-4-yl)-6-fluoroindole,

(7) 1-(piperidin-4-yl)-6-bromoindole,

(8) 1-(piperidin-4-yl)-6-nitroindole,

(9) 1-(piperidin-4-yl)-6-methoxyindole, and

(10) 1-(piperidin-4-yl)-6-acetamidomethylindole.

Examples of the dosage forms of the compounds of the present inventioninclude oral preparations such as powders, fine granules, granules,tablets, coated tablets and capsules, external preparations such asointments, patches and suppositories, and injections. These preparationsmay be produced by the conventional methods with the use ofpharmaceutical carriers commonly employed in the art.

Namely, oral preparations may be produced by blending the1,4-substituted cyclic amine derivative or a pharmacologicallyacceptable salt thereof with fillers optionally together with binders,disintegrating agents, lubricating agents, coloring agents, corrigents,etc. and then processing the resultant blends into powders, finegranules, granules, tablets, coated tablets, capsules, etc. by theconventional methods.

As the fillers, use may be made of, for example, lactose, corn starch,sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicondioxide. As the binders, use may be made of, for example, polyvinylalcohol, polyvinyl ether, methylcellulose, ethylcellulose, acacia,tragacanth, gelatin, shellac, hydroxypropylmethylcellulose,hydroxypropylcellulose, polyvinylpyrrolidone, polypropyleneglycol/polyoxyethylene block polymers and meglumine. As thedisintegrating agents, use may be made of, for example, starch, agar,gelatin powder, crystalline cellulose, calcium carbonate, sodiumhydrogencarbonate, calcium citrate, dextrin, pectin and calciumcarboxymethylcellulose. As the lubricating agents, use may be made of,for example, magnesium stearate, talc, polyethylene glycol, silica andhardened vegetable oils. As the coloring agents, use may be made ofthose authorized as pharmaceutical additives. As the corrigents, use maybe made of, for example, cocoa powder, mentha, aromatic powder, menthaoil, borneol and powdered cinnamon bark. Needless to say, these tabletsand granules may be appropriately coated with sugar, etc., if necessary.

Injections are produced by blending the 1,4-substituted cyclic aminederivative or a pharmacologically acceptable salt thereof with pHregulating agents, resolvents, tonicity agents, etc., optionallytogether with dissolution aids, stabilizers, etc. and processing theresultant blends into preparations by the conventional methods.

External preparations may be produced by the conventional methodswithout restriction. As the bases, therefore, use can be made of variousmaterials commonly used in drugs, quasi drugs, cosmetics, etc.

Particular examples of the base materials include animal and vegetableoils, mineral oils, ester oils, waxes, higher alcohols, fatty acids,silicone oils, surfactants, phospholipids, alcohols, polyhydricalcohols, water-soluble polymers, clay minerals and purified water. Ifneeded, it is possible to further add pH regulating agents,antioxidants, chelating agents, antiseptics, fungicides, coloringagents, perfumes, etc., though the materials usable as the base in theexternal preparations of the present invention are not restrictedthereto. If necessary, it is also possible to furthermore add otheringredients capable of inducing differentiation, blood flowaccelerators, bactericides, antiinflammatory agents, cell activators,vitamins, amino acids, humectants, keratolytic agents, etc. The abovematerials may be added in such amounts as to give the concentrationsthereof commonly employed in the production of external preparations.

The clinical dose of the 1,4-substituted cyclic amine derivative of thepresent invention or a pharmacologically acceptable salt thereof is notrestricted but varies depending on the symptoms, severity, age,complications, etc. Also, the dose thereof varies depending on the typeof the salt, administration route, etc. In general, these compounds areadministered to an adult in a dose of from 0.01 to 1000 mg, preferablyfrom 0.1 to 500 mg and still preferably from 0.5 to 100 mg, per dayorally, intravenously, as suppositories or percutaneously.

Next, the results of a binding test on the compounds of the presentinvention to serotonin 1A and serotonin 2 receptors will be given so asto illustrate the effects of the present invention. Moreover, theresults of a binding test on these compounds to an al adrenalin receptorwill be given so as to illustrate the safety thereof.

It is reported in, for example, the following publications thatcompounds with a serotonin antagonism are usable as medicament fortreating, ameliorating and preventing spastic paralysis or centralmuscle relaxants for ameliorating myotonia:

(1) Saishin Igaku Jiten, 3rd impression of 1st edition, p. 809“SEROTONIN”, Iyaku Shuppan

(2) Stedman's Medical Dictionary, 24th edition, p. 1227 “serotonin”,Williams & Wilkins

(3) Shinkei Shinpo, 37(3), 459-467, 1993.

(4) Iyaku Journal, 30(8), 2030-2068, 1994.

(5) DN & P, 5(8), 453-460, 1992.

(6) Annals of Neurology, 30(4), 533-541, 1991.

Compounds poor in the ability to bind to an α1 adrenalin receptor aremedicines which would scarcely affect blood pressure in orthostatichypotension, etc. and have a higher safety.

Effect of the Invention:

(1) Binding test on serotonin 1A, serotonin 2 and α1 adrenalin receptors

Method

(Reagent)

The following reagents were employed in this test.

1) Serotonin binoxalate (5-HT binoxalate, mfd. by Sigma Chemical Co.).

2) Methysergide maleate (mfd. by RBI).

As radioisotope-labeled compounds, use was made of the followingreagents (mfd. by NEN).

3) [³H] 8-Hydroxy-dipropylaminotetralin (8-OH-DPAT).

4) [³H] Ketanserin hydrochloride.

5) [³H] Prazosin.

These compounds and test compounds, when insoluble in water, weredissolved in ethanol and then dilutedwith distilled water so as to eachgive an ethanol concentration of 10%. Methysergide maleate was dissolvedin distilled water before using.

(Animal)

Use was made of SD rats aged 6 to 8 weeks.

(Preparation of receptor source)

The rats were sacrificed by dcapitation to extirpate the cerebra. Thehippocampus and cortex were separated therefrom and employed in thebinding tests respectively on the serotonin 1A receptor and theserotonin 2 receptor.

The hippocampus was mixed with 50 times (on the wet weight basis) asmuch a 0.32 M sucrose solution while the cortex was mixed with 10 timesas much the same solution. Each mixture was homogenized by using aTeflon glass homogenizer and centrifuged at 1,000×g for 10 min. Thesupernatant thus obtained was further centrifuged at 20,000×g for 20min. The obtained precipitate was re-suspended in 50 times (based on theintial wet weight; in the case of the hippocampus) or 10 times (in thecase of the cortex) as much a 50 mM Tris hydrochloride (pH 7.4) andincubated at room temperature for 30 min. After centrifuging at 20,000×gfor 20 min, the obtained precipitate was further suspended andcentrifuged twice each in the same manner. The precipitate thus obtainedwas suspended in 100 times (based on the initial wet weight; in the caseof the hippocampus) or 20 times (in the case of the cortex) as much a 50mM Tris hydrochloride solution (pH 7.4) to thereby give a receptorfraction. This receptor fraction was stored at −80° C. until using.

(Binding test on [³H] 8-hydroxy-dipropylaminotetralin)

To the receptor fraction of the hippocampus were added a test compoundand 0.5 nM of [³H] 8-hydroxy-dipropylaminotetralin and the resultantmixture was incubated at room temperature for 30 min. Next, it wasfiltered through a glass filter with the use of a cell harvester. Afterwashing the glass filter with 50 mM Tris hydrochloride (pH 7.4), theradioactivity of the receptor was measured with a liquid scintillationcounter. The binding detected in the presence of 10 μM of serotoninbinoxalate was referred to as the nonspecific binding.

(Binding test on [³H] ketanserin)

To the receptor fraction of the cerebral cortex were added a testcompound and 0.3 nM of [³H] ketanserin and the resultant mixture wasincubated at 37° C. for 15 min. Next, it was filtered through a glassfilter with the use of a cell harvester. After washing the glassfilterwith 50 mM Tris hydrochloride (pH 7.4), the radioactivity of thereceptor was measured with a liquid scintillation counter. The bindingdetected in the presence of 1 μM of methysergide was referred to as thenonspecific binding.

IC₅₀ was calculated by the probit method, while Ki was determined inaccordance with the following formula:Ki=IC ₅₀/(1+c/Kd)wherein c represents the concentration of the radioisotope-labeledcompound, and Kd represents the dissociation constant of theradioisotope-labeled compound with respect to-the receptor determined byScatchard's analysis.(Binding test on [³H] prazosin)

To the receptor fraction of the cerebral cortex were added a testcompound and about 0.2 nM of [³H] prazosin and the resultant mixture wasincubated at room temperature for 60 min. Next, it was filtered througha glass filter with the use of a cell harvester. After washing the glassfilter with 50 mM Tris hydrochloride (pH 7.4), the radioactivity of thereceptor was measured with a liquid scintillation counter. The bindingdetected in the presence of 10 μM of phentolamine was referred to as thenonspecific binding.

The following tables show the abilities of typical examples of thecompounds of the present invention to bind to the serotonin 1A andserotonin 2 receptors, wherein the number of each compound correspondsto the Example number. Also, comparison was made with cyproheptadinehydrochloride (CAS Registry No.: 969-33-5) and cyclobenzaprinehydrochloride (CAS Registy No.: 6202-23-9) which were employed aspositive controls having anti-serotonin effects.

TABLE 1 5HT1a 5HT2 5HT1a 5HT2 Ex. no. (nM) (nM) Ex. no. (nM) (nM) 1623.94 >200 28 46.90 8.10 3 28.70 17.40 29 — 36.50 4 6.00 24.90 30 21.9015.70 5 10.10 8.10 31 20.80 4.10 6 4.50 17.40 32 30.20 30.20 7 34.3012.80 33 5.70 24.30 8 13.50 26.90 34 1.90 9.10 9 3.00 11.60 35 16.6037.60 10 8.10 6.00 36 4.50 14.90 11 5.70 27.90 37 4.60 14.80 12 8.5016.30 38 15.00 21.80 13 24.20 >200 39 1.60 8.90 15 28.60 28.60 4043.66 >200 16 109.32 13.85 41 19.81 5.03 17 19.01 16.36 42 35.80 5.70 180.13 0.12 43 4.20 37.90 19 8.80 7.00 44 4.00 43.70 20 15.20 0.22 4515.20 6.40 21 1.90 42.70 46 1.10 4.20 22 24.00 12.20 47 206.20 92.30 237.40 14.60 48 15.30 35.00 24 26.50 174.20 49 54.50 29.90 25 8.30 13.1050 31.20 52.20 26 2.90 19.50 52 2.50 5.60 27 >200 28.80 53 21.50 2.10

TABLE 2 5HT1a 5HT2 5HT1a 5HT2 Ex. no. (nM) (nM) Ex. no. (nM) (nM) 547.10 10.30 81 44.30 119.00 55 41.90 17.80 82 71.20 5.30 56 20.70 1.7084 >200 133.70 57 14.60 1.10 85 169.60 56.20 58 26.20 34.80 99 — 8.70 5912.00 28.90 102 2.70 28.40 60 60.80 >200 103 3.90 15.80 61 5.00 12.50104 2.40 6.00 62 6.20 7.40 105 >200 17.40 63 3.20 1.20 106 0.70 6.40 6414.80 14.20 107 7.70 1.70 65 8.80 4.80 108 172.30 2.20 66 50.90 85.00110 23.30 16.00 67 262.50 27.10 111 5.50 74.20 68 47.20 39.50 112 3.20165.20 69 9.70 29.90 113 13.70 >200 70 41.90 27.60 114 5.80 23.20 7125.40 28.20 116 0.50 14.30 72 25.90 21.10 117 0.60 10.70 73 34.90 7.20118 0.70 10.40 75 3.60 30.30 119 0.20 45.50 76 43.20 >200 120 1.00 11.2077 44.50 13.70 121 0.50 22.80 78 2.40 29.60 122 0.20 15.20 79 115.4026.50 123 251.10 2.70

TABLE 3 5HT1a 5HT2 5HT1a 5HT2 Ex. no. (nM) (nM) Ex. no. (nM) (nM) 1241.10 45.80 152 16.40 0.27 125 0.10 4.76 153 15.48 4.24 126 1.23 129.30154 6.52 0.0006 127 0.21 5.08 155 14.83 1.33 128 0.34 4.70 156 7.80 2.60129 0.95 0.65 157 4.11 0.18 130 0.49 9.12 158 8.18 0.16 131 0.17 15.21159 5.58 0.76 132 2.08 14.27 160 3.86 8.00 133 3.70 0.05 161 3.23 0.43136 3.40 6.20 162 0.98 27.08 137 0.65 6.68 163 2.41 7.75 138 1.98 5.93164 0.54 34.06 139 2.31 8.80 165 5.50 1.22 140 6.23 35.07 166 0.79 17.07141 3.03 342.74 167 6.49 18.43 143 1.86 3.36 168 3.84 4.06 144 1.49 3.38169 16.39 13.78 145 8.07 48.77 170 47.45 16.26 146 163.97 >200 171 0.39178.00 147 1.31 0.77 172 0.12 52.43 148 9.58 0.25 173 0.06 70.07 1497.44 0.50 174 0.24 1.85 150 13.00 0.16 175 1.49 0.35 151 8.84 0.57 1761.67 0.05

TABLE 4 5HT1a 5HT2 5HT1a 5HT2 Ex. no. (nM) (nM) Ex. no. (nM) (nM) 1770.25 0.92 204 1.06 4.49 178 10.17 2.53 205 2.76 0.12 179 0.17 0.41 2061.49 2.17 181 1029.00 9.62 207 0.81 2.69 182 4.28 2.91 208 2.33 1.05 1831.18 3.86 209 6.98 4.72 184 15.13 3.06 210 2.50 4.93 185 14.58 4.73 2110.53 1.21 186 14.55 3.32 212 0.82 0.36 187 65.03 5.01 213 1.03 0.18 1897.72 2.02 214 3.50 0.90 190 0.49 0.33 215 126.40 1.00 191 29.06 0.32 2164.70 42.90 192 1.02 2.90 218 4.50 11.70 193 6.92 2.88 219 19.60 30.90194 4.59 >200 221 1.90 2.40 195 5.73 1.15 222 0.04 18.10 196 1.67 1.17224 3.09 5.11 197 10.40 1.27 225 5.74 7.61 198 13.70 2.21 228 0.34 >200199 1.98 1.19 229 2.50 >200 200 4.84 233.98 230 13.30 >200 201 7.05 >200232 37.65 48.19 202 2.57 5.13 233 0.60 >200 203 0.55 4.61 234 1.10 3.30

TABLE 5 5HT1a 5HT2 5HT1a 5HT2 Ex. no. (nM) (nM) Ex. no. (nM) (nM) 2350.20 14.60 262 1.50 2.10 236 29.20 10.60 263 0.46 >200 237 30.40 >200264 11.30 138.90 238 86.60 >200 265 25.20 34.20 240 >200 27.60 266 31.6022.60 241 360.00 1658.30 277 22.80 3.90 242 >200 2.30 278 >200 3.90243 >200 53.00 279 0.22 90.40 244 >200 2.50 281 35.19 11.20 245 >20011.20 282 58.70 150.00 246 >200 60.00 283 39.50 40.90 247 >200 52.90 2844.50 4.70 248 2.90 6.80 285 0.44 1.39 249 2.10 20.20 286 3.74 3.12 2501.60 18.80 287 0.10 >200 251 58.50 >200 288 0.2 0.1 254 >200 176.80 2916.9 100.6 255 >200 15.70 292 92.0 58.8 256 0.40 12.10 A 25 29 257 2.800.61 B 29.5 1.68 258 35.20 4.80 C 72.5 0.4 259 0.60 5.90 A:Cyclobenzaprine 260 1.30 12.90 B: Cyproheptadine 261 1.50 5.30 C: Co.No. 5 given in WO96/ 23784 294 1.05 2.86 318 1.49 8.3 295 0.85 3.64 3190.56 24.5 296 0.32 2.73 320 0.55 44 297 0.98 4.17 321 0.14 >20 298 1.8621.3 322 0.08 30.36 299 0.11 2.54 323 0.14 >20 300 1.73 3.55 324 0.1 >20301 0.8 21.93 325 0.65 10.86 302 2.92 60.48 326 0.4 >20 303 3.6 35.85327 1.04 2.64 304 8.37 6.26 328 2.06 >20 305 0.06 3.29 329 2.06 2.41 3062.82 3.87 330 0.11 >20 307 7.02 0.83 331 0.11 8.28 308 0.73 3.84 3322.24 16.17 309 3.85 1.02 333 1.08 >20 310 1.34 2.29 334 0.04 >20 3111.08 46.39 335 0.22 >20 312 8.27 0.56 336 <0.2 >20 313 13.07 1.58 337<0.2 >20 314 0.72 1.1 338 0.07 >20 315 6.74 1.18 339 <0.2 >20 316 1.821.26 317 0.76 >20 340 3.02 2.84 370 >20 >20 341 2.08 0.67 372 >20 >20342 0.65 38.15 373 0.24 1.77 343 1.54 1.64 375 1.56 3.37 344 1.78 1.64376 0.91 2.1 345 4.82 0.29 378 14.2 1.54 346 13.46 1.49 379 9.65 1.25347 2.24 0.65 380 2.87 1.56 349 0.22 8.12 381 1.37 2.02 350 1.92 11.44382 7.59 3.31 351 0.27 >20 383 5.34 1.81 352 1.58 0.75 384 0.13 0.25 3530.78 12.57 385 2.41 0.97 354 1.22 4.79 386 5.38 >20 355 0.35 6.87 38763.5 >20 356 1.52 >20 388 2.26 >20 357 0.38 1.3 389 0.53 15.46 358 0.7314.02 390 0.99 11.56 359 0.71 7.39 391 1.72 6.83 360 26.6 >20 392 0.6538.15 361 0.27 >20 393 0.85 2.54 362 0.46 3.54 394 1.18 0.96 363 1.53.39 397 1.28 2.27 364 1.73 4.23 365 0.42 3.11 366 0.48 2.05 367 1.631.76 368 1.63 0.56 369 2.02 2.88

Subsequently, the abilities of typical examples of the compounds of thepresent invention to bind to the α1 adrenalin receptor were evaluated bythe test method described above. The following table shows the results,wherein the number of each compound corresponds to the Example number.

Also, comparison was made with Co. No. 5, as a typical example of theknown compounds with a serotonin antagonism, discolsed in Table 2 ofWO96/23784 and having the following chemical formula. This compound wasproduced in accordance with the mehtod described in WO96/23784 (seeReferential Example 1 as will be given hereinbelow).

TABLE 6

Ex. no. α1 (nM) 9 76.5 11 147 13 188 19 55.5 22 113 26 51.1 36 39 38244.2 42 230 65 55.7 68 223.4 75 88.6 77 248.7 103 77.7 106 71.3 12158.2 125 46.37 133 261.65 137 125.59 147 156.84 149 304.15 151 292.16162 222.63 164 638.02 166 193.71 168 72.56 182 70.07 184 188.42 187 >200189 442.24 197 68.59 204 183.23 206 104.75 216 81.59 235 77.8 236 72.2248 75.3 250 263 277 354.41 280 222 283 197 285 26.8 291 171.5 292 178.3Cyclobenzaprine — Cyproheptadine 1900 Co. No. 5 given in 16.8 WO96/23784294 80.7 295 195.3 296 238.5 297 226.3 298 27.9 300 224.6 301 66.9 302142.9 303 306.9 304 141 305 35.9 306 147.5 307 51.5 308 59.4 309 122.9310 84.4 311 85 312 53.3 313 144 314 51.3 316 63.7 317 400 318 46.6 31942.5 320 26.1 321 203 322 41.3 323 86.9 324 60.9 325 47 326 167 327 99328 140 329 149 330 338.7 331 77 332 65.9 333 247.1 334 212.2 335 28.4336 53.7 338 21.3 339 31.7 340 339.8 341 47.6 342 25 343 38.1 344 74.9345 103.2 346 115.5 347 44.3 349 88.5 350 123.4 351 175 352 96.7 353144.1 354 90.5 355 39.5 358 41.8 359 75.9 360 690 361 77.4 362 144 363106 364 289 365 61.6 366 74.6 367 45.8 368 37.6 369 121.4 370 255.5 372206.4 375 61.4 376 46.7 378 43.7 379 30.3 380 116 381 100.7 382 163.1383 120.1 385 21.6 386 26.2 387 26.2 388 365.8 389 45 390 34.3 391 116.2392 25 393 37.8 397 27.1

Tables 1 to 6 indicate that the 1,4-substituted cyclic amine derivativesof the present invention are useful as medicaments with a serotoninantagonism and have clinical usefulness and a high safety, inparticular, those for treating, ameliorating and preventing spasticparalysis or central muscle

-   -   relaxants for ameliorating myotonia.

Moreover, the compounds of the present invention are superior in safetyto the Co. No.5 disclosed in WO96/23784 which is a typical example ofthe known compounds, since the compounds in the present invention havelow abilities to bond to the α1 adrenalin receptor and scarcely affectblood pressure.

(2) Morphine induced Straub's tail phenomenon in mice

By using mice, typical examples of the compounds of the presentinvention were evaluated in the effect of relaxing rigidity inaccordance with the method reported in Drug Dev. Res., 11:53-57, 1987.

In this test, use was made of male ddY mice aged 4 to 5 weeks (SLC,Shizuoka) which were divided into groups each comprising 8 animals.Also, use was made, as positive controls, of cyproheptadinehydrochloride, cylcobenzaprine hydrochloride, tizanidine hydrochloride(CAS Registry No.: 51322-75-9) and baclofen (CAS Registry No.:1134-47-0). The test compounds and the positive controls were eachdissolved in a 5% glucose solution for injection or suspended in a 0.5%methylcellulose solution. Morphine hydrochloride was dissolved inphysiological saline for injection.

The test compounds of the given concentrations were administered per os(p.o.) or intraperitoneally (i.p.) to the mice, while the media wereorally administered to the control group. After 15 min of theadministration of the test compounds, 12.5 mg/kg of morphinehydrochloride was subcutaneously injected into the animals. After 15, 30and 45 min of the administration of morphine hydrochloride, thehyper-muscle tone in the tail was observed and those showinghyper-muscle tone were judged as positive in Straub's tail reaction.

The rate of those showing Straub's tail reaction in each test group wascompared with that of the control group at each observation point andanalyzed by the χ square calibration method to thereby determine thestatistically significant (p<0.05) minimal effective dose.

Now, the results of the evaluation will be shown.

TABLE 7 Ex. i.p. p.o. i.p. p.o. no. (mg/kg) (mg/kg) Ex. no. (mg/kg)(mg/kg) 9 10 — 168 — 10 22 — >10 182 — 10 34 ≦10 30 184 — 3 36 1 ≦3 186— 10 42 ≦10 10 189 — 10 65 — 30 197 — 10 103 ≦10 >30 204 3 3 106 10 >30206 — 10 121 — 10 235 — >10 125 1 3 248 ≦10 30 133 0.3 ≦0.3 250 10 30137 — 1 277 <1 30 147 ≦0.3 ≦3 285 1 1 149 1 ≦3 Cyclobenzaprine 10 — 151— 3 Cyproheptadine 3 — 162 1 >10 Tizanidine 1 1 166 3 3 Baclofen 3 10

As Table 7 clearly shows, the compounds of the present invention haveexcellent effects of relaxing rigidity in vivo.

To further illustrate the present invention in greater detail, thefollowing Production Examples and Examples will be given. However, it isneedless to say that the present invention is not restricted thereto.

PRODUCTION EXAMPLE

Production Example 1: Synthesis of 4-flourophenethyl bromide

Triphenylphosphine (222 g) and N-bromosuccinimide (151 g) were added toa solution of 4-fluorophenethyl alcohol (100 g) in methylene chloride(1 1) under ice cooing, followed by stirring for 1 hr. Afterconcentrating the resultant solution under reduced pressure, theprecipitated crystals were filtered off and the filtrate wasconcentrated to give the title compound (133 g) as a colorless oil(yield: 92%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 3.14(2H, t, J=8 Hz), 3.54(2H, t, J=8 Hz), 6.98-7.03(2H, m),7.15-7.18(2H, m).Production Example 2 Synthesis of 1-bromo-1-(4-fluorophenyl)-propane

Thionyl chloride (6.8 ml) was added dropwise into ethanol (20 ml) underice cooling, followed by stirring for 15 min. Then3-(4-fluorophenyl)propionic acid (2.853 g) was added to the resultantsolution, which was stirred at room temperature for 11 hr andconcentrated under reduced pressure. The residue was diluted with ethylacetate (500 ml), washed with a saturated aqueous solution of sodiumbicarbonate and brine (a saturated aqueous solution of sodium chloride),dried over anhydrous sodium sulfate, and then concentrated under reducedpressure to give a colorless oil (3.456 g). The product was dissolved intetrahydrofuran (90 ml) and lithium aluminum hydride (0.863 g) was addedto the solution under ice cooling. After stirring the mixture for 1 hr,water (0.9 ml), a 5 N aqueous solution of sodium hydroxide (0.9 ml) andfurther water (2.7 ml) were added thereto. The resulting precipitate wasfiltered off and the filtrate was concentrated under reduced pressure togive a pale yellow oil (2.577 g). This oil was treated as in Example 1to give the title compound (2.354 g) as a yellow oil (yield: 63.6%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.14(2H, tt, J=6.6, 7.0 Hz), 2.76(2H, t, J=7.0 Hz), 3.38(2H, t,J=6.6 Hz), 6.98(2H, t, J=8.8 Hz), 7.16(2H, m).

Production Example 3: Synthesis of 1-bromo-4-(4-flourophenyl)-butane

(3-1) 3-(4-Flourophenyl)propyl -1,1-dicarboxylic acid

Sodium (0.7 g) was dissolved in ethanol (17.5 ml) and diethyl malonate(9.1 ml) and 4-fluorophenethyl bromide (4.1 g) were added thereto. Thenthe resultant mixture was heated under reflux for 2.5 hr and allowed tocool. Next, it was diluted with ethyl acetate (500 ml), washed withbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was dissolved in ethanol (10 ml) followedby the addition of potassium hydroxide (10.2 g) dissolved in water (10ml) thereto. The resultant mixture was stirred at 80° C. for 3 hr. Afterallowing to cool, it was acidified with hydrochloric acid, diethyl etherwas added thereto. The organic layer was separated and washed withbrine, dried over anhydrous magnesium sulfate. It was then concentratedunder reduced pressure to give the title compound (6.938 g) as a paleyellow oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.25(2H, dt, J=7.6 Hz), 2.70(2H, t, J=7.6 Hz), 3.42(1H, t, J=7.6Hz), 6.97(2H, t, J=8.8 Hz), 7.12(2H, m).(3-2) 4-(4-Fluorophenyl)butyric acid

The above 3-(4-fluorophenyl)propyl-1,1-dicarboxylic acid (6.938 g) wasstirred at 180° C. for 40 min to give the title compound (4.877 g) as abrown oil.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.94(2H, m), 2.37(2H, t, J=7.6 Hz), 2.65(2H, t, J=7.6 Hz),6.97(2H, t, J=8.8 Hz), 7.15(2H, m).(3-3) Ethyl 4-(4-fluorophenyl)butyrate

Under ice cooling, thionyl chloride (6.8 ml) was dropped into ethanol(20 ml) and the resultant solution was stirred at room temperature for11 hr and concentrated under reduced pressure. Next, it was diluted withethyl acetate (500 ml) washed with a saturated aqueous solution ofsodium bicarbonate and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give the title compound (7.178 g)as a brown oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.34(3H, dt, J=2.0, 7.0 Hz), 1.93(2H, m), 2.31(2H, dt, J=0, 7.2Hz), 2.63(2H, t, J=7.2 Hz), 4.12(2H, dq, J=2.0, 7.0 Hz), 6.97(2H, t,J=8.8 Hz), 7.13(2H, m).(3-4) 4-(4-Fluorophenyl)butan-1-ol

The above ethyl 4-(4-fluorophenyl)butyrate (7.178 g) was dissolved intetrahydrofuran (120 ml) and then aluminum lithium hydride (1.55 g) wasadded thereto under ice cooling followed by stirring for 1 hr. Afteradding water (1.5 ml), 5 N aqueous solution of sodium hydroxide (1.5 ml)and further water (4.5 ml), the resulting precipitate was filtered offand the filtrate was concentrated under reduced pressure to give thetitle compound (3.890 g) as a brown oil.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.58-1.71(4H, m), 2.61(2H, t, J=7.0 Hz), 3.66(2H, dt, J=2.8, 6.4Hz), 6.96(2H, t, J=8.8 Hz), 7.13(2H, m).(3-5) 1-Bromo-4-(4-fluorophenyl)butane

The above 4-(4-fluorophenyl)butan-1-ol (7.178 g) was treated as in theabove Production Example 1 to give the title compound (4.250 g) as ayellow oil (yield: 91.9%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.75(2H, m), 1.88(2H, m), 2.62(2H, t, J=7.6 Hz), 3.42(2H, t,J=7.0 Hz), 6.97(2H, t, J=8.8 Hz), 7.13(2H, m).Production Examnple 4 Syntbpsis of 4-bromophenethyl bromide

4-Bromophenethyl alcohol (1.3 ml) was treated as in Production Example 1to give the title compound (2.345 g) as a pale yellow oil (yield:88.8%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 3.12(2H, t, J=7.4 Hz), 3.54(2H, t, J=7.4 Hz), 7.09(2H, d, J=8.4Hz), 7.45(2H, d, J=8.4 Hz).Produiction Example 5 Synthesis of 3-chlorophenethyl bromide

3-Chlorophenethyl alcohol (1.0 ml) was treated as in Production Example1 to give the title compound (1.417 g) as a pale yellow oil (yield:64.6%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.14(2H, t, J=8.6 Hz), 3.56(2H, t, J=8.6 Hz), 7.11(1H, m),7.21(1H, s), 7.45 (2H, m).Production Example 6 Synthesis of 4-chlorophenethyl bromide

4-Chlorophenethyl alcohol (5 ml) was treated as in Production Example 1to give the title compound (2.639 g) as a pale yellow oil (yield:32.6%).

(no NMR)

Production Example 7 Synethesis of 4-methoxyphenethyl bromide

4-Methoxyphenethyl alcohol (0.61 g) was treated as in Production Example1 to give the title compound (0.838 g) as a pale yellow oil (yield:97.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.10(2H, t, J=7.6 Hz), 3.53(2H, t, J=7.6 Hz), 3.80(3H, s),6.86(2H, d, J=8.2 Hz), 7.13(2H, d, J=8.2 Hz).Production Example 8 Synthesis of 4-(2-bromoethyl)benzyl) alcohol

(2-Bromoethyl)benzaldehyde (1.178 g) was dissolved in ethanol (20 ml)After adding sodium borohydride (0.189 g) the resultant mixture wasstirred at room temperature for 1 hr. Then it was diluted with ethylacetate (200 ml), washed with brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate system) to givethe title compound (0.439 g) as a pale yellow oil (yield: 40.1%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 2.02(1H, br-s), 3.16(2H, t, J=7.6 Hz), 3.56(2H, t, J=7.6 Hz),7.20(2H, d, J=8.4 Hz), 7.31(2H, d, J=8.4 Hz).Production Example 9 Synthesis of 4-(2-bromoethyl-benzaldehyde

(2-Bromoethyl)benzene (2.72 ml) was dissolved in methylene chloride (20ml). Subsequently, a 1.0 M solution (40 ml) of titanium tetrachloride inmethylene chloride and dichloromethyl methyl ether (2.72 ml) weresuccessively added dropwise thereinto while maintaining the reactiontemperature at −10° C. or below. After stirring at room temperature for6 hr, the reaction solution was poured into ice, extracted with ethylacetate, washed successively with a saturated aqueous solution of sodiumchloride, a saturated aqueous solution of sodium bicarbonate and asaturated aqueous solution of sodium chloride again, dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive the title compound (5.408 g) as a brown oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.26(2H, t, J=7.2 Hz), 3.61(2H, t, J=7.2 Hz), 7.40(2H, d, J=8.4Hz), 7.86(2H, d, J=8.4 Hz), 10.01(1H, s).Production Example 10 Synthesis of 4-(2-bromoethyl)-benzaldoxime

The above 4-(2-bromoethyl)benzaldehyde (2.72 g) was dissolved in ethanol(80 ml). After adding water (20 ml), hydroxylamine hydrochloride (1.53g) and sodium acetate trihydrate (2.99 g), the resultant mixture washeated under reflux for 30 min. Then it was allowed to cool and thereaction mixture was partitioned between water and ethyl acetate (500ml). The organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to give the titlecompound (5.408 g) as a brown oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.18(2H, t, J=7.4 Hz), 3.57(2H, t, J=7.4 Hz), 7.24(2H, d, J=8.0Hz), 7.52(2H, d, J=8.0 Hz), 8.13(1H, s).Prodction Example 11 Synthesis of 4-cyanonphenethyl bromide

4-(2-Bromoethyl)benzaldoxime (1.0 g) was treated as in Example 20 togive the title compound (0.977 g) as a brown oil.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 3.23(2H, t, J=7.2 Hz), 3.59(2H, t, J=7.2 Hz), 7.34(2H, d, J=7.4Hz), 7.63(2H, d, J=7.4 Hz).Production Example 12 Synthesis of 4-carbamoylphenethyl bromide

4-Cyanophenethyl bromide (0.997 g) was dissolved in sulfuric acid (20ml) and stirred at room temperature for 15 hr. Then it was poured intoice, diethyl ether was added thereto and the layers were separated. Theorganic layer was washed with a saturated aqueous solution of sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate system) to give thetitle compound (0.619 g) as colorless crystals (yield: 62.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.23(2H, t, J=7.3 Hz), 3.59(2H, t, J=7.3 Hz), 7.31(2H, d, J=8.4Hz), 7.78(2H, d, J=8.4 Hz).Production Example 13 Synthesis ofN-isopropyl-4-(2-bromoethyl)phenylacetamide (13-1)N-Isopropyl-4-bromophenylacetamide

4-Bromophenylacetic acid (10 g) was dissolved in tetrahydrofuran (200ml). After adding N,N-carbonyl-diimidazole (7.54 g) thereto, theresultant mixture was stirred at room temperature for 15 min. Next,isopropylamine (3.96 ml) was further added and the resultant mixture wasstirred at room temperature for 24 hr and then concentrated underreduced pressure. The residue was partitioned between ethyl acetate (500ml) and a saturated aqueous solution of sodium bicarbonate, the organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give colorless crystals (11.3 g)of the title compound (yield: 94.8%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.08 (6H, d, J=6.8 Hz), 3.47 (2H, s), 4.06 (1H, m), 5.17(1H,br-s), 7.13(2H, d, J=8.8 Hz), 7.47(2H, d, J=8.8 Hz).

(13-2) N-Isopropyl-4-vinylphenylacetamide

N-Isopropyl-4-bromophenylacetamide (1.0 g) and vinyltributyltin (1.4 ml)were dissolved in toluene (12 ml). After addingtetrakistriphenylphosphinepalladium (0.5 g) thereto, the resultantmixture was heated under reflux for 4 hr. Then it was allowed to cooland diluted with ethyl acetate. The resulting solid was filtered off andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give colorless crystals (0.578 g) of the titlecompound (yield: 72.8%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.08(6H, d, J=6.4 Hz), 3.55(2H, s), 4.07(1H, m), 5.21 (1H, br-s),5.28 (1H, dd, J=0.8, 10.8 Hz), 5.76 (H, dd, J=0.8, 17.6 Hz), 6.718(1H,dd, J=10.8, 17.6 Hz), 7.21(2H, J=8.0 Hz), 7.40(2H, d, J=8.8 Hz).(13-3) N-Isopropyl-4-(2-hydroxyethyl)phenylacetamide

N-Isopropyl-4-vinylphenylacetamide (0.378 g) was dissolved intetrahydrofuran (4.4 ml). Under ice cooling, a 1.0 M solution (5.6 ml)of a borane/tetrahydrofuran complex in tetrahydrofuran was addeddropwise thereinto and then the resultant mixture was stirred for 2 hr.After adding a 5 N aqueous solution (3 ml) of sodium hydroxide and a 30%aqueous solution (3 ml) of hydrogen peroxide, the mixture was stirredfor 10 hr. Then ethyl acetate and water were added thereto and themixture was distributed between two liquid layers. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate-methanol system) to givecolorless crystals (0.134 g) of the title compound (yield: 32.6%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.08(6H, dd, J=1.6, 6.8 Hz), 2.87(2H, t, J=6.6 Hz) 3.51(2H, s),3.87 (2H, t, J=6.6 Hz), 4.07 (1H, m), 5.26(1H, br-s) 7.19(2H, J=8.6 Hz),7.22(2H, d, J=8.6 Hz).(13-4) N-Isopropyl-4-(2-bromoethyl)phenylacetamide

N-Isopropyl-4-(2-hydroxyethyl)phenylacetamide (0.134 g) was treated asin production Example 1 to give colorless crystals (0.029 g) of thetitle compound (yield: 16.9%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.08(6H, d, J=6.4 Hz), 3.16(2H, t, J=7.4 Hz), 3.15(2H, s),3.57(2H, t, J=7.4 Hz), 4.06(1H, m), 5.20(1H, br-s) 7.21(4H,Production Example 14 Synthesis of3-[2-(t-butyl)dimethyl-silyloxyethoxy]phenethyl bromide

[wherein TBDMS means (t-butyl)dimethylsilyl.]

3-Hydroxyphenethyl alcohol (1.5 g) and1-bromo-2-(t-butyl)dimethylsilyloxyethane (3.4 g) were treated as inExample 35 to give a pale yellow oil. Then this product was treated asin the above Production Example 1 to give the title compound (1.996 g)as a pale yellow oil (yield: 55.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.11(6H, s), 0.92(9H, s), 3.13(2H, t, J=7.6 Hz), 3.56(2H, t,J=7.6 Hz), 3.97(2H, m), 4.04(2H, m), 6.78(3H, m), 7.21(1H, m).

Production Example 19 Synthesis of 1,2-dihydroxymethyl)-4-bromobenzene

(15-1) Dimethyl 4-bromophthalate

Methanol (500 ml) was added to 4-bromophthalic anhydride (50.25 g).Further, chlorosulfonic acid (1 ml) was added thereto. The resultantmixture was heated under reflux overnight and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(39.98 g) as a colorless oil (yield: 66.1%).

¹H-NMR (400 MHZ, CDCl₃):

δ(ppm) 3.90(3H, s), 3.92(3H, s), 7.63(1H, d, J=8.4 Hz), 7.68(1H, dd,J=2.0, 8.4 Hz), 7.84(1H, d, J=2.0 Hz).(15-2) 1,2-Dihydroxymethyl-4-bromobenzene

Lithium aluminum hydride (8.77 g) was suspended in tetrahydrofuran (400ml) and the obtained suspension was stirred under ice cooling. Into theresultant suspension was added dropwise a solution of dimethyl4-bromophthalate (39.98 g) in tetrahydrofuran (100 ml). After stirringfor additional 30 min, water (8.8 ml), a 5 N aqueous solution ofsodiumhydroxide (8.8 ml) and further water (26.4 ml) were successivelyadded thereto. The resultant mixture was diluted with ethyl acetate andthe insoluble matter was filtered off followed by concentration underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(13.7 g) as a colorless powder (yield: 43.1%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 3.18(1H, br-t), 3.27(1H, br-t), 4.63-4.65(2H, m), 7.20(1H, d,J=8.0 Hz), 7.43(1H, dd, J=2.0, 8.0 Hz), 7.49(1H, d, J=2.0 Hz).

Production Example 1 6 Synthesis of3,4-di[t-butyl)dimethyl-silyloxymethyl]phenethyl bromide

(16-1) 3,4-Di[(t-butyl)dimethylsilyloxymethyl]phenethyl alcohol

1,2-Dihydroxymethyl-4-bromobenzene (3.110 g) was treated as reported inJ. Am. Chem. Soc., 6190 (1972). togiveacolorless oil (6.000 g). Thisproduct was dissolved in tetrahydrofuran (56 ml) and a solution (4.2 ml)of n-butyllithium in n-hexane and ethylene oxide (1.36 ml) weresuccessively added thereto in a nitrogen atmosphere at −78° C. followedby stirring for 3 hr. After adding water and diethyl ether to separatethe layers, the organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound-(2.214 g) as a colorless oil(yield: 37.6%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.11(6H, s), 0.95(9H, s), 2.87(2H, t, J=6.4 Hz), 3.85(2H, q,J=6.4 Hz), 4.72(2H, s), 4.74 (2H, s), 7.11(1H, dd, J=1.6, 7.6 Hz),7.29(1H, d, J=1.6 Hz), 7.36(1H, d, J=7.6 Hz).(16-2) 3,4-Di[(t-butyl)dimethylsilyloxymethyl]phenethyl bromide

Pyridine (0.16 ml) was added to 3,4-dihydroxymethylphenethyl alcohol(0.41 g) and the resultant mixture was treated as in the aboveProduction Example 1 to give the title compound (0.421 g) as a colorlessoil (yield: 88.9%).

¹H-NMR (400 MHZ, CDCl₃):

δ(ppm) 0.11 (6H, s), 0.95(9H, s), 3.16 (2H, t, J=7.8 Hz), 3.56(2H, t,J=7.8 Hz), 4.71(2H, s), 4.74(2H, s), 7.10(1H, dd, J=1.6, 7.6 Hz),7.27(1H, d, J=1.6 Hz), 7.36(1H, d, J=7.6 Hz).

Production Example 17 Synthesis of3-(t-butyl)-dimethylsiloxymethyl]phenyl bromide

(17-1) 3-(t-Butyl)dimethylsilyloxymethylbenzyl alcohol

1,3-Benzenedimethanol (10 g) was dissolved in tetrahydrofuran (210 ml).Under ice cooling, sodium hydride (1.16 g) was added thereto. Next,(t-butyl)dimethyl-chlorosilane (4.36 g) dissolved in tetrahydrofuran (40ml) was added dropwise thereinto and the resultant mixture was stirredat room temperature for 3 hr. After adding water, the resultant mixturewas concentrated under reduced pressure. After adding ethyl acetate (200ml) to the residue, the organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound (2.108 g) as a colorless oil(yield: 29.1%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 0.10(6H, s), 0.95(9H, s), 1.57(1H, br-s), 4.70(2H, s), 4.75(2H,s), 7.23-7.35(4H, m).(17-2) 3-(t-Butyl)dimethyldilyloxymethylbenzaldehyde

Dimethyl sulfoxide (1.43 ml) was dissolved in methylene chloride (31ml). In a nitrogen atmosphere, oxalyl chloride (0.88 ml) was addeddropwise thereinto at −78° C. and the resultant mixture was stirred for30 min. After successively adding thereto3-(t-butyl)dimethylsilyloxymethylbenzyl alcohol (2.108 g) dissolved inmethylene chloride (10 ml) and diisopropylethylamine (4.4 ml), theobtained mixture was stirred at room temperature for 1 hr. Then thereaction solution was concentrated under reduced pressure and purifiedby silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (2.132 g) as a colorless oil (yield: 100%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 0.12(6H, s), 0.95(9H, s), 4.81(2H, s), 7.50(1H, t, J=7.6 Hz),7.61(1H, d, J=7.6 Hz), 7.77(1H, d, J=7.6 Hz), 7.83(1H, s), 10.02 (H, s).(17-3) 3-(t-Butyl)dimethyldilyloxymethylstyrene

Methyltriphenylphosphonium bromide (3.16 g) was suspended intetrahydrofuran (30 ml). Under ice cooling, potassium t-butoxide (0.99g) was added thereto and the resultant mixture was stirred at roomtemperature for 10 min. Then it was ice cooled again followed by theaddition of 3-(t-butyl)dimethyl silyloxybenzaldehyde (2.132 g) dissolvedin tetrahydrofuran (0.88 ml). The resultant mixture was stirred at roomtemperature for 5 hr. After adding water and ethyl acetate, the layerswere separated and the organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound (1.930 g) as a yellow oil(yield: 93.0%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 0.10(6H, s), 0.95(9H, s), 4.74(2H, s), 5.24(1H, dd, J=1.2, 11.2Hz), 5.75(1H, dd, J=1.2, 17.6 Hz), 6.72(1H, dd, J=11.2, 17.6 Hz),7.21(1H, m), 7.29(2H, m), 7.38(1H, S).(17-4) 3-(t-Butyl)dimethylsilyloxymethylphenethyl alcohol

By using a 0.5 M solution of (9-boranebicyclo-[3.3.1]nonane) intetrahydrofuran, 3-(t-butyl)dimethylsilyloxymethylstyrene (0.5 g) wastreated as reported in J. Am. Chem. Soc., 7765 (1974). to give the titlecompound (0.494 g) as a colorless oil (yield: 92.2%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 0.110(6H, S), 0.95(9H, s), 2.88(2H, t, J=6.4 Hz), 3.87(2H, q,J=6.4 Hz), 4.73(2H, s), 7.09-7.34(4H, m).(17-5) 3-(t-Butyl)dimethylsilyloxymethylphenethyl bromide

3-(t-Butyl)dimethylsilyloxymethylphenethyl alcohol (0.494 g) was treatedas in the above Production Example 1 to give the title compound (0.390g) as a colorless oil (yield: 63.7%).

Production Example 18 Synthesis of4-[2-(t-butyl)-dimethyldilyloxyethyl]phenethyl bromide

(18-1) Dimethyl 1,4-phenylenediacetate

Under ice cooling, thionyl chloride (6.6 ml) was added dropwise intomethanol (26 ml) and the resultant mixture was stirred for 15 min. Next,1,4-phenylenediacetic acid (5.0 g) was added thereto and the resultantmixture was stirred at room temperature for 35 hr and then concentratedunder reduced pressure. Then it was diluted with ethyl acetate (500 ml),washed with a saturated aqueous solution of sodium bicarbonate andbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to give the title compound as colorless crystals.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.61(4H, s), 3.69(6H, s), 7.25(4H, d, J=6.4 Hz)(18-2) 1,4-Benzenediethanol

All the dimethyl 1,4-phenylenediacetate synthesized in ProductionExample 18-1 was dissolved in tetrahydrofuran (100 ml). Under icecooling, lithium aluminum hydride (2.44 g) was added thereto and theresultant mixture was stirred at room temperature for 3 hr. Then it wasice cooled and water (2.5 ml), a 5 N aqueous solution of sodiumhydroxide (2.5 ml) and further water (7.5 ml) were added thereto. Theresulting precipitate was filtered off and the filtrate was concentratedunder reduced pressure to give the title compound (4.555 g) as colorlesscrystals.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.40(2H, t, J=6.0 Hz), 2.85(4H, t, J=6.4 Hz), 3.86(4H, q, J=6.4Hz), 7.19 (4H, s)(18-3) 4-[2-t-Butyl)dimethylsilyloxyethyl]phenethyl alcohol

1,4-Benzenediethanol (4.555 g) was treated as in the above ProductionExample 17-1 to give the title compound (0.869 g) as a colorless oil(yield: 30.1%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) −0.01(6H, s), 0.91(9H, s), 2.80(2H, t, J=7.2 Hz), 2.84(2H, t,J=6.4 Hz), 3.79(2H, t, J=7.2 Hz), 3.84(2H, q, J=6.4 Hz), 7.15(4H, s).(18-4) 4-[2-(t-Butyl)dimethyldilyloxyethyl]phenethyl bromide

4-[2-(t-Butyl)dimethylsilyloxyethyl]phenethyl alcohol (0.869 g) wastreated as in the above Production Example 1 to give the title compound(0.700 g) as a colorless oil (yield: 65.8%).Production Example 19 Synthesis of 4-(1-hydroxyethyl)-phenethyl bromide

4-(2-Bromoethyl)benzaldehyde (3.245 g) was dissolved in tetrahydrofuran(60 ml). Under ice cooling, a 3 M solution (4.9 ml) of methylmagnesiumbromide in diethyl ether was added dropwise thereinto and the resultantmixture was stirred for 1.5 hr. After adding water and ethyl acetate,the layers were separated and the organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was then purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(2.745 g) as a brown oil (yield: 83.8%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.49(3H, d, J=6.4 Hz), 1.81(1H, br-s), 3.16(2H, t, J=7.6 Hz),3.57 (2H, t, J=7.6 Hz), 4.89 (1H, q, J=6.4 Hz), 7.20 (2H, d), 7.33(2H,d).

Production Example 20 Synthesis of 4-methanesulfonyl-phenethyl bromide

(20-1) 4-2t-Butyldimethylsiloxyethyl)-1-bromobenzene

A solution of 4-bromophenethyl alcohol (10 g), imidazole (4.0 g) and(t-butyl)dimethylsilyl chloride (9.0 g) in dimethylformamide (50 ml) wasstirred at room temperature for 3 hr. Then the reaction solution wasconcentrated under reduced pressure. After adding water and ethylacetate, the layers were separated and the organic layer was washed withbrine and dried over anhydrous magnesium sulfate. After evaporating thesolvent, the residue was purified by silica gel column chromatography(hexane/ethyl acetate system) to give the title compound (13.9 g) as acolorless oil (yield: 88%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) −0.02(6H, s), 0.89(9H, s), 2.79(2H, t, J=7 Hz), 3.80(2H, t, J=7Hz), 7.10(2H, d, J=8 Hz), 7.42(2H, d, J=8 Hz).(20-2) 4-Methanesulfonylphenethyl alcohol

A 2.5 M solution (7.6 ml) of (n-butyllithium) in hexane was addeddropwise at −78° C. into a solution of4-[2-(t-butyl)-dimethylsiloxyethyl]-1-bromobenzene (5.0 g) intetrahydrofuran (50 ml) over 10 min. After 10 min, a saturated solutionof sulfur dioxide in tetrahydrofuran (200 ml) was added thereto and theresultant mixture was warmed to room temperature. After concentratingthe reaction solution under reduced pressure, dimethylformamide (100 ml)and methyl iodide (2.7 g) were added to the obtained residue followed bystirring at 50° C. for 6 hr. After concentrating under reduced pressure,a saturated aqueous solution of sodium bicarbonate and ethyl acetatewere added thereto and the layers were separated. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. To the residue was addedtetrahydrofuran and tetrabutylammonium fluoride followed by stirring at0° C. for 2 hr. After adding water and ethyl acetate to the reactionsolution, the layers were separated and the organic layer was washedwith brine and dried over anhydrous magnesium sulfate. The residue waspurified by silica gel column chromatography (methylene chloride/ethanolsystem) to give the title compound (1.9 g) as a colorless oil (yield:60%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.45(1H, t, J=7 Hz), 2.85(2H, t, J=7 Hz), 3.04(3H, s), 3.92(2H,q, J=7 Hz), 7.44(2H, d, J=8 Hz), 7.89(2H, d, J=8 Hz).(20-3) 4-Methanesulfonylphenethyl bromide

4-Methanesulfonylphenethyl alcohol (1.9 g) was treated as in the aboveProduction Example 1 to give the title compound (1.9 g) as a colorlessoil (yield: 76%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.05(3H, s), 3.27(2H, t, J=7 Hz), 3.61(2H, t, J=7 Hz), 7.43(2H,d, J=8 Hz), 7.90(2H, d, J=8 Hz).Production Example 21 Synthesis of 4-sulfamoylphenethyl bromide

Under ice cooling, phenethyl bromide (5.0 g) was added dropwise intochlorosulfonic acid (15 ml) followed by stirring for 1 hr. The reactionsolution was diluted with ice water and ethyl acetate and the layerswere separated. Then the organic layer was washed with brine. Thenaqueous ammonia (10 ml) was added thereto and the resultant mixture wasstirred for 1 hr. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Thecrystalline precipitates were washed with isopropyl ether and air-driedto give the title compound (1.4 g) as white crystals (yield: 22%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 3.20(2H, t, J=7 Hz), 3.31(2H, br-s), 3.77(2H, t, J=7 Hz),7.48(2H, d, J=8 Hz), 7.74(2H, d, J=8 Hz).Production Example 22 Synthesis of 1-bromo-3-(4-fluoro-phenoxy)propane

A mixture of 4-fluorophenol (11 g), 1,3-dibromopropane (61 g), sodiumhydroxide (8.0 g), tetra-n-butylammonium bromide (6.0 g), methylenechloride (200 ml) and water (200 ml) was vigorously stirred at roomtemperature overnight. After separating the organic layer, it was washedwith brine and dried over anhydrous magnesium sulfate. The residue wasthen purified by silica gel column chromatography (hexane/isopropylether system) to give the title compound (16.5 g) as a colorless oil(yield: 71%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.24-2.36(2H, m), 3.60(2H, t, J=7 Hz), 4.08(2H, t, J=7 Hz),6.80-6.89(2H, m), 6.93-7.00(2H, m).Production Example 23 Synthesis of3-bromopropoxy-1,2-methylenedioxybenzene

3,4-Methylenedioxyphenol (4.144 g) was dissolved inN,N-dimethylformamide (40 ml). Under ice cooling, 60% sodium hydride(1.2 g) was added thereto and the resultant mixture was stirred. After 1hr, 1,3-dibromopropane (9.1 ml) was added thereto followed by stirringat room temperature overnight. The reaction mixture was diluted withethyl acetate and water and the layers were separated. Then the organiclayer was washed with water, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane system) to give thetitle compound (1.341 g) as a colorless solid (yield: 17%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.25-2.32(2H, m), 3.59(2H, t, J=6.4 Hz), 4.03(2H, t, J=5.8 Hz),5.92(2H, s), 6.33(1H, dd, J=8.8 Hz, 2.4 Hz), 6.49(1H, d, J=2.4 Hz),6.71(1H, d, J=8.8 Hz).Production Example 24 Synthesis of 4-(3-bromopropoxy)-phenethyl alcohol

4-Hydroxyphenethyl alcohol (4.145 g), 1,3-dibromopropane (9.1 ml) andtetrabutylammonium bromide (967 mg) were added to methylene chloride(100 ml) and a solution of sodium hydroxide (2.4 g) in water (100 ml)and the resultant mixture was vigorously stirred at room temperatureovernight. The methylene chloride layer was washed with water, driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane system) to give the title compound (1.005 g) as acolorless solid (yield: 13%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.31(2H, qui, J=6 Hz), 2.81(2H, t, J=6.4 Hz), 3.60(2H, t, J=6.4Hz), 3.83(2H, t, J=6.4 Hz), 4.09(2H, t, J=6 Hz), 6.86(2H, d, J=8.6 Hz),7.08(2H, d, J=8.6 Hz).Production Example 25 Synthesis of 4-(3-bromopropoxy)benzyl alcohol

4-Hydroxybenzyl alcohol (3.724 g) was treated as in the above ProductionExample 24 to give the title compound (314 mg) as a pale yellow solid(yield: 4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.31(2H, qui, J=6.3 Hz), 3.30(2H, t, J=6.3 Hz), 4.10(2H, t, J=6.3Hz), 4.60(2H, d, J=5.8 Hz), 6.90(2H, d, J=8.9 Hz), 7.30(2H, d, J=8.9Hz).

Production Example 26 Synthesis of 3-(2-bromoethyl)pyridine

(26-1) 3-Pyridylethanol

Ethyl 3-pyridylacetate (2.0 ml) was dissolved in tetrahydrofuran (66ml). Under ice cooling, lithium aluminum hydride (0.5 g) was addedthereto followed by stirring for 30 min. After adding water (0.5 ml), a5 N aqueous solution of sodium hydroxide (0.5 ml) and further water (1.5ml), the resulting precipitate was filtered off and washed with ethylacetate. The filtrate was concentrated under reduced pressure to givethe title compound (1.636 g) as a pale yellow oil (1.636 g) (yield:quantitative).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.84(2H, t, J=6.4 Hz), 3.85(2H, t, J=6.4 Hz), 7.20(1H, m),7.57(1H, m), 8.36(2H, m)(26-2) 3-(2-Bromoethyl)pyridine

3-Pyridylethanol (0.4 g) was treated as in the above ProductionExample 1. The liquid reaction mixture was reverse extracted with 1 Nhydrochloric acid and then basified with an aqueous solution of sodiumhydroxide. Next, it was extracted with chloroform, washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to give the title compound (0.481 g) as abrown oil (yield:79.5%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.18(2H, t, J=7.2 Hz), 3.58(2H, t, J=7.2 Hz), 7.47(1H, m),7.55(1H, dt, J=1.6, 7.2 Hz), 7.67(1H, ddd, J=1.6, 7.2, 10.8 Hz),8.51(1H, m).

Production Example 27 Synthesis of1-bromo-2-(2-methoxy-pyridin-5-yl)ethane

(27-1) 2-(2-Methoxypyridin-5-yl)ethanol

5-Bromo-2-methoxypyridine (2.628 g) synthesized as reported inTetrahedron, 1373 (1985). was dissolved in diethyl ether (40 ml) andthen treated as in the above Production Example 16-1 to give the titlecompound (1.342 g) as a pale yellow oil (yield: 62.7%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 2.79 (2H, t, J=6.4 Hz), 3.82 (2H, br-t), 3.91(3H, s), 6.71(1H, d,J=8.4 Hz), 7.46(1H, dd, J=2.4, 8.4 Hz), 8.01(1H, d, J=2.4 Hz).(27-2) 1-Bromo-2-(2-methoxypyridin-5-yl)ethane

2-(2-Methoxypyridin-5-yl)ethanol (1.342 g) was treated as in the aboveProduction Example 1. After the completion of the reaction, reverseextraction method was effected to give the title compound (1.221 g) as abrown oil (yield: 64.5%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.09(2H, t, J=7.4 Hz), 3.52(2H, t, J=7.4 Hz), 3.93(3H, s),6.71(1H, d, J=8.4 Hz), 7.44(1H, dd, J=2.4, 8.4 Hz), 8.02(1H, d, J=2.4Hz).

Production Example 28 Synthesis of 1-bromo-2-(2-cyanopyridin-5-yl)ethane

(28-1) 2-(3-Pyridyl)ethanol

3-Pyridylacetic acid hydrochloride (25 g) was treated successively as inthe above Production Examples 3-3 and 3-4 to give the title compound(16.938 g) as a yellow oil (yield: 95.5%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.86(2H, t, J=6.8 Hz), 3.88(2H, t, J=6.8 Hz), 7.22(1H, dd, J=4.8,7.6 Hz), 7.527(1H, d, J=7.6 Hz), 8.42(1H, dd, J=2.0, 4.8 Hz), 8.44(1H,d, J=2.0 Hz).(28-2) 2-(Pyridyl)-1-triphenylmethyloxyethane

2-(3-Pyridyl)ethanol (5.0 g) was treated as reported in TetrahedronLett., 579 (1986). to give the title compound (10.096 g) as a yellow oil(yield: 68.0%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 2.86(2H, t, J=6.4 Hz), 3.32(2H, t, J=6.4 Hz), 7.08-7.38(16H, m),7.53(1H, d, J=8.0 Hz), 8.46(2H, m).(28-3) 3-(2-Triphenylmethyloxyethyl)pyridin N-oxide

2-(3-Pyridyl)-1-triphenylmethyloxyethane (10.096 g) was treated asreported in Tetrahedron Lett., 1475 (1986). to give the title compound(11.201 g) as a yellow oil (yield: quantitative).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 2.86(2H, t, J=6.4 Hz), 3.32(2H, t, J=6.4 Hz), 7.08-7.38(16H, m),7.53(1H, d, J=8.0 Hz), 8.46(2H, m).(28-4) 2-(2-Cyanopyridin-5-yl)-1-triphenylmethyloxyethane

2-Cyano-5-(2-triphenylmethyloxyethyl)pyridine N-oxide (8.0 g) andtrimethylsilyl cyanide (11.2 ml) were treated as reported in Synthesis,314 (1983). to give the title compound (2.831 g) as a pale yellow oil(yield: 30.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.91(2H, t, J=6.0 Hz), 3.38(2H, t, J=6.0 Hz), 7.20-7.35(16H, m),7.60(2H, m), 8.55(1H, s).(28-5) 2-(2-(Cyanopyridin-5-yl)ethanol

2-(2-Cyanopyridin-5-yl)-1-triphenylmethyloxyethane (2.631 g) and formicacid (38.0 ml) were treated as reported in Tetrahedron Lett., 579(1986). to give the title compound (0.455 g) as colorless crystals(yield: 45.7%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 2.95(2H, t, J=5.8 Hz), 3.94(2H, t, J=5.8 Hz), 7.64(1H, d, J=8.0Hz), 7.75(1H, dd, J=2.0, 8.0 Hz), 8.61(1H, d, J=2.0 Hz)(28-6) 1-Bromo-2-(2-cyanopyridin-5-yl)ethane

2-(2-Cyanopyridin-5-yl)ethanol (0.423 g) was treated as in the aboveProduction Example 1 to give the title compound (0.406 g) as colorlesscrystals (yield: 67.3%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 3.30(2H, t, J=6.8 Hz), 3.94(2H, t, J=6.8 Hz), 7.71(1H, d, J=8.0Hz), 7.78(1H, dd, J=2.4, 8.0 Hz), 8.62(1H, d, J=2.4 Hz).

Production Example 29 Synthesis of5-(2-bromoethyl)-3-(t-butyl)dimethylsilyloxymethylpyridine

(29-1) Methyl 5-bromonicotinate

5-Bromonicotinic acid (10 g) and methanol were treated as in the aboveProduction Example 3-3 to give the title compound (10.052 g) ascolorless crystals (yield: 94.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.97(3H, s), 8.44(1H, dd, J=1.6, 2.4 Hz), 8.85(1H, d, J=2.4 Hz),9.13(1H, d, J=1.6 Hz).(29-2) 5-Bromo-3-hydroxymethylpyridine

Methyl 5-bromonicotinate (5.0 g) and methanol were treated as in theabove Production Example 3-4 to give the title compound (3.410 g) as ayellow oil (yield: 78.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.50(1H, m), 3.97(2H, s), 7.90(1H, s), 8.48(1H, s), 8.58(1H, s).(29-3) 5-Bromo-3-(t-butyldimethylsilyloxymethyl)pyridine

5-Bromo-3-hydroxymethylpyridine (3.41 g), imidazole (13.33 g),t-butyldimethylchlorosilane (13.57 g) and N,N-dimethylformamide (63 ml)were treated as reported in J. Am. Chem. Soc., 6190 (1972) to give thetitle compound (5.605 g) as a yellow oil (yield: quantitative).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.12(6H, s), 0.95(9H, s), 4.74(2H, s), 7.81(1H, s), 8.47(1H, s),8.56(1H, s).(29-4) 5-(2-Hydroxyethyl)-3-(t-butyl)dimethylsilyloxymethylpyridine

5-Bromo-3-(t-butyl)dimethylsilyloxymethylpyridine (3.41 g) and diethylether employed as a solvent were treated as in the above ProductionExample 16-1 to give the title compound (0.827 g) as a brown oil (yield:26.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.12(6H, s), 0.95(9H, s), 1.61(1H, m), 2.88(2H, t, J=6.4 Hz),3.89(2H, q, J=6.4 Hz), 4.75(2H, s), 7.54(1H, s), 8.38(1H, s), 8.43(1H,s).(29-5) 5-(2-Bromoethyl)-3-(t-butyl)dimethylsilyloxymethylpyridine

5-(2-Hydroxyethyl)-3-(t-butyl)dimethylsilyloxymethylpyridine (0.4 g) wastreated as in the above Production Example 1 to give the title compound(0.248 g) as a yellow oil (yield: 50.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.12(6H, s), 0.95(9H, s), 3.18(2H, t, J=7.2 Hz), 3.57(2H, t,J=7.2 Hz), 4.76(2H, s), 7.53(1H, s), 8.38(1H, d, J=2.0 Hz), 8.46(1H, d,J=2.0 Hz).Production Example 30 Synthesis of 5-(2-bromoethyl)-3-methoxypyridine

Methoxymethyltriphenylphosphonium chloride (3.0 g) was suspended intetrahydrofuran (10 ml). Under ice cooling, potassium t-butoxide (0.98g) was added thereto followed by stirring for 15 min. Next,5-methoxy-3-pyridinecarboxy-aldehyde (0.4 g) synthesized as reported inHeterocycles, 2159 (1987). and dissolved in tetrahydrofuran (5 ml) wasadded thereto and the resultant mixture was stirred at room temperaturefor 2 hr. After adding water and ethyl acetate thereto, the layers wereseparated and the organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give a yellow oil (0.364 g). This product wasdissolved in 1 N hydrochloric acid (44 ml) and stirred at 60° C. for 3hr. After allowing to cool, the reaction solution was basified with anaqueous solution of sodium hydroxide, extracted with chloroform, washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to give a yellow oil (0.220 g). This product wasdissolved in ethanol (7.2 ml) and sodium tetrahydroborate (0.054 g) wasadded thereto under ice cooling. After stirring at room temperature for30 min, the resultant mixture was diluted with ethyl acetate, washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to give a pale yellow oil (0.188 g). This productwas treated as in the above Production Example 1 to give the titlecompound (0.181 g) as a brown oil (yield: 28.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.16(2H, t, J=6.4 Hz), 3.57(2H, t, J=6.4 Hz), 3.88(3H, s),7.08(1H, s), 8.10(1H, s), 8.21(1H, s).Production Example 31 Synthesis of 2-(2-bromoethyl)thiophene

2-Thienylethanol (0.44 ml) was treated as in the above ProductionExample 1 to give the title compound (0.490 g) as a colorless oil(yield: 64.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.38(2H, t, J=7.6 Hz), 3.58(2H, t, J=7.6 Hz), 6.89(1H, d, J=1.2Hz), 6.96(1H, d, J=4.2 Hz), 7.19(1H, dd, J=1.2, 4.2 Hz).Production Example 32 Synthesis of 3-(2-bromoethyl)thiophene

3-Thienylethanol (0.45 ml) was treated as in the above ProductionExample 1 to give the title compound (0.389 g) as a pale yellow oil(yield: 59.9%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm)3.21(2H, t, J=7.6 Hz),3.57(2H,t, J=7.6 Hz), 6.98(1H, d, J=4.8 Hz),7.09(1H, s), 7.29(1H, d, J=4.8 Hz).

Production Example 33 Synthesis of 2-(2-bromoethyl)thiazole

(33-1) 2-(2-Hydroxyethyl)thiazole

Thiazole (5.0 g) was dissolved in diethyl ether (150 ml) and treated asin the above Production Example 16-1 to give the title compound (1.173g) as a brown oil (yield: 15.5%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.24(2H, t, J=6.0 Hz), 4.02(2H, m), 7.23(1H, d, J=3.4 Hz),7.69(1H, d, J=3.4 Hz).(33-2) 2-(2-Bromoethyl)thiazole

2-(2-Hydroxyethyl)thiazole (1.173 g) was treated as in the aboveProduction Example 1 to give the title compound (0.362 g) as a paleyellow oil (yield: 24.9%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm)3.57(2H, t, J=7.2 Hz),3.75(2H,t, J=7.2 Hz), 7.26(1H, d, J=3.4 Hz),7.74(1H, d, J=3.4 Hz).

Production Example 34 Synthesis of 6-(2-bromoethyl)benzothiazole

(34-1) 2-Amino-6-ethoxycarbonylmethylbenzothiazole

Ethyl 4-aminophenylacetate (18 g) was dissolved in acetic acid (120 ml)and ethyl thiocyanate (29.3 g) was added thereto. Under ice cooling,bromine (6.2 ml) was added dropwise thereinto over 45 minutes whilemaintaining the reaction temperature at about 10° C. After thecompletion of the addition, the resultant mixture was stirred at roomtemperature for 1.5 hr and then at 80° C. for about 2 hr until thereaction was completed. Then the reaction solution was poured into icewater, basified with an 8 N aqueous solution of sodium hydroxide,extracted with chloroform, washed with water, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure to givethe title compound (22.23 g) as orange crystals (yield: 93.66%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.26(3H, t, J=7.2 Hz), 3.65(2H, s), 4.16(2H, q, J=7.2 Hz),5.31(2H, br-s), 7.22(1H, dd, J=2.0, 8.4 Hz), 7.48(1H, d, J=8.4 Hz),7.53(1H, d, J=2.0 Hz).(34-2) Ethyl (6-benzothiazolyl)acetate

2-Amino-6-ethoxycarbonylmethylbenzothiazole (2.0 g) was dissolved inN,N-dimethylf ormamide (17 ml) and isoamyl nitrite (2.3 ml) was addeddropwise into the solution at 65° C. Then the resultant mixture wasstirred as such for 15 min. After allowing to cool, the reactionsolution was poured into ice water, extracted with ethyl acetate, washedwith brine, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(1.341 g) as an orange oil (yield: 71.6%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.26(3H, t, J=7.2 Hz), 3.77(2H, s), 4.18(2H, q, J=7.2 Hz),7.45(1H, d, J=8.4 Hz), 7.90(1H, s), 8.09(1H, d, J=8.4 Hz), 8.97(1H, s).(34-3) 6-(2-Hydroxyethyl)benzothiazole

Ethyl (6-benzothiazolyl)acetate (0.22 g) was treated as in the aboveProduction Example 18-2 to give the title compound (0.130 g) as a brownoil (yield: 72.5%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.14(1H, m), 3.01(2H, t, J=6.4 Hz), 3.93(2H, t, J=6.4 Hz),7.36(1H, dd, J=1.6, 8.4 Hz), 7.81(1H, d, J=1.6 Hz), 8.02(1H, d, J=8.4Hz), 8.97(1H, s).(34-4) 6-(2-Bromoethyl)benzothiazole

6-(2-Hydroxyethyl)benzothiazole (0.130 g) was treated as in the aboveProduction Example 1. Then the reaction solution was directly purifiedby silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (0.080 g) as a yellow oil (yield: 45.5%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.32(2H, t, J=7.6 Hz), 3.64(2H, t, J=7.6 Hz), 7.37(1H, dd, J=1.6,8.4 Hz), 7.82(1H, d, J=1.6 Hz), 8.09(1H, d, J=8.4 Hz), 8.97(1H, s).Production Example 35 Synthesis of (5-methoxy-2-thienyl)ethyl bromide

A 2.5 M solution (23 ml) of n-butyllithium in hexane was added dropwiseat −78° C. into a solution of 2-methoxythiophene (5.0 g) in ether (50ml). Then the resultant mixture was warmed to room temperature andstirred. After 10 min, ethylene oxide (2.5 g) was added dropwisethereinto at −78° C. and then the resultant mixture was warmed to roomtemperature and stirred for 1 hr. After adding a saturated aqueoussolution of ammonium chloride and ethyl acetate, the layers wereseparated and the organic layer was washed with brine, dried overanhydrous magnesium sulfate and purified by silica gel columnchromatography (hexane/ethyl acetate system). Then it was diluted withmethylene chloride (50 ml) and triphenylphosphine (4.0 g) andN-bromosuccinimide (2.7 g) were added thereto under ice cooling followedby stirring overnight. After concentrating under reduced pressure, theresulting crystalline precipitates were filtered off and the filtratewas concentrated to give the title compound (1.7 g) as a brown oil(yield: 18%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.19(2H, t, J=7 Hz), 3.51(2H, t, J=7 Hz), 3.85(3H, s), 6.01(1H,d, J=4 Hz), 6.47(1H, d, J=4 Hz).Production Example 36 Synthesis of (2-methoxy-5-thiazolyl)ethyl bromide

2-Methoxythiazole (3.9 g) was treated as in the above Production Example35 to give the title compound (1.4 g) as a brown oil (yield: 19%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.20(2H, t, J=7 Hz), 3.51(2H, t, J=7 Hz), 4.03(3H, s), 6.89(1H,s).

Production Example 37 Synthesis of (2-cyano-5-thiazolyl)-ethyl bromide

(37-1) (2-Formyl-5-thiazolyl)ethyl bromide

A solution of 2-formylthiazole (5.0 g), trimethylene glycol (6.7 g) andp-toluenesulfonic acid (0.5 g) in toluene (100 ml) was heated underreflux overnight. Then a saturated aqueous solution of sodiumbicarbonate was added to the reaction solution and the layers wereseparated. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas diluted with ether (200 ml). Then a 2.5 M solution (23 ml) ofn-butyllithium in hexane was dropped at −78° C. thereinto followed bywarming to room temperature and stirring. After 10 min, ethylene oxide(2.5 g) was added dropwise thereinto at −78° C. and then the resultantmixture was warmed to room temperature and stirred for 1 hr. Afteradding a saturated aqueous solution of ammonium chloride and ethylacetate thereto, the layers were separated and the organic layer waswashed with brine, dried over anhydrous magnesium sulfate and purifiedby silica gel column chromatography (hexane/ethyl acetate system). Thenit was diluted with methylene chloride (50 ml) and triphenylphosphine(3.9 g) and N-bromosuccinimide (2.7 g) were added thereto under icecooling followed by stirring overnight. After concentrating underreduced pressure, the resulting crystalline precipitates were filteredoff and the filtrate was concentrated. The residue was diluted withtetrahydrofuran (20 ml) and 2 N hydrochloric acid (30 ml) was addedthereto. After heating under reflux for 1 day, the reaction solution wasbasified by adding an aqueous solution of sodium hydroxide. After addingethyl acetate thereto, the layers were separated and the organic layerwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was then purified bysilica gel column chromatography (hexane/ethyl acetate system) to givethe title compound (2.5 g) as a brown oil (yield: 26%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.40(2H, t, J=7 Hz), 3.78(2H, t, J=7 Hz), 7.94(1H, s), 9.93(1H,s).(37-2) (2-Cyano-5-thiazolyl)ethyl bromide

A suspension of the above (2-formyl-5-thiazolyl)ethyl bromide (2.5 g),hydroxylammonium chloride (0.79 g) and anhydrous sodium acetate (1.87 g)in ethanol (50 ml) was stirred at room temperature for a day. Thereaction solution was diluted with ethyl acetate and water and thenbasified with an 8 N aqueous solution of sodium hydroxide followed byseparation of an organic layer. The organic layer was washed with brineand dried over anhydrous magnesium sulfate. After evaporating thesolvent, the residue was diluted with methylene chloride (50 ml)followed by the addition of triethylamine (2.3 g). Thentrifluoromethanesulfonic anhydride (3.2 g) was added dropwise thereintoat −78° C. and the resultant mixture was heated to room temperature.After adding a saturated aqueous solution of sodium bicarbonate andchloroform thereto, the layers were separated and the organic layer wasdried over anhydrous magnesium sulfate and purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(0.2 g) as a brown oil (yield: 8.1%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.40(2H, t, J=7 Hz), 3.76(2H, t, J=7 Hz), 7.87(1H, s).

Production Example 38 Synthesis of 1-(2-bromoethyl)-4-bromopyrazole

(38-1) 1-(2-Hydroxyethyl)-4-bromopyrazole

1-(2-Benzyloxyethyl)-4-bromopyrazole (1.078 g) was dissolved in ethanol(20 ml). After adding conc. hydrochloric acid (15 ml), the resultantmixture was stirred at 80° C. for 10 hr. After allowing to cool, it wasconcentrated under reduced pressure followed by the addition of asaturated aqueous solution of sodium bicarbonate. Then the resultantmixture was extracted with ethyl acetate and the organic layer waswashed with water, dried over magnesium sulfate and concentrated underreduced pressure to give the title compound (525 mg) as a colorless oil(yield: 71%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.30(1H, br-s), 3.90(2H, t, J=5 Hz), 4.15(2H, t, J=5 Hz ),7.40(1H, s), 7.45(1H, s).(38-2) 1-(2-Bromoethyl)-4-bromopyrazole

1-(2-Hydroxyethyl)-4-bromopyrazole (525 mg) was treated as in the aboveProduction Example 1 to give the title compound (200 mg) as a colorlessoil (yield: 30%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.61(2H, t, J=6.2 Hz), 4.62(2H, t, J=6.2 Hz), 7.50(1H, s),7.51(1H, s).Production Example 39 Synthesis of 1-(2-benzyloxyethyl)-4-bromopyrazole

4-Bromopyrazole (2.205 g) was dissolved in tetrahydrofuran (20 ml).Under ice cooling, 60% sodium hydride (625 mg) was added theretofollowed by stirring. After 30 min, benzyl 2-bromoethyl ether (3.872 g)obtained from 2-benzyloxyethanol in the same manner as the one ofProduction Example 1 was added thereto and the resultant mixture wasstirred at room temperature overnight. Then the reaction solution waspartitioned between ethyl acetate and water and the organic layer waswashed with water, dried over magnesium sulfate and concentrated underreduced pressure to give the title compound (2.287 g) as a colorless oil(yield: 53%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3. 79 (2H, t, J=5.4 Hz), 4.29 (2H, t, J=5.4 Hz), 4.48 (2H, s),7.22-7.48(5H, m), 7.46(1H, s), 7.52(1H, s).

Production Example 40 Synthesis of1-[2-(4-fluorophenyl)-ethyl]-3-methyl-4-piperidone

(40-1) Bis(methylpropionyl)-4-fluorophenethylamine

4-Fluorophenethylamine (236.87 g) was dissolved in methanol (360 ml) andice cooled. Then methyl acrylate (360 ml) was added dropwise thereintoover 30 min followed by heating under reflux for 10 hr. Afterconcentrating under reduced pressure, the title compound (527.04 g) wasobtained as a colorless oil (yield: 99.5%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.43(4H, t, J=7.6 Hz), 2.62-2.83(4H, m), 2.83(4H, t, J=7.6 Hz),3.66(6H, s), 6.95(2H, t, J=8.8 Hz), 7.12(2H, dd, J=4.8, 8.8 Hz).(40-2) 1-Fluorophenethyl-3-methoxycarbonyl-4-piperidone (sodium salt)

Under ice cooling, 60% sodium hydride (75 g) was suspended in toluene(1400 ml) and heated to a reaction temperature of 110° C. Then a portion(30 ml) of a solution of bis-(methylpropionyl)-4-fluorophenethylamine(263.52 g) in toluene (100 ml) was added dropwise thereinto.Subsequently, methanol (3.2 ml) was added dropwise into the resultantmixture to cause a little evolution of gas and then the mixture wasstirred at room temperature until the evolution was ceased. The reactionsolution was heated again and a portion (5 ml) of the above solution ofbis(methylpropionyl)-4-fluorophenethyl-amine (263.52 g) in toluene (100ml) was added dropwised thereinto. After the completion of the addition,the resultant mixture was stirred for 30 min and then ice cooled. Afteradding water (800 ml), the precipitate was collected by filtration,washed with water (700 ml), toluene (500 ml) and hexane (500 ml) anddried to give the title compound (255.0 g) as pale yellow crystals(yield: quantitative).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.96(2H, t, J=6.0 Hz), 2.51(2H, m), 2.72(2H, t, J=7.6 Hz),3.15(2H, s), 3.39(3H, s), 7.08(2H, t, J=8.8 Hz), 7.26(2H, dd, J=6.0, 8.8Hz).(40-3) 1-Fluorophenethyl-4-piperdone

Hydrochloric acid (500 ml) and toluene (500 ml) were added to1-fluorophenethyl-3-methoxycarbonyl-4-piperidone (sodium salt) and theresultant mixture was heated under reflux at 130° C. for 15.5 hr. Thenthe reaction solution was ice cooled and basified by adding sodiumhydroxide. Next, it was extracted with ethyl acetate, washed with brine,dried over anhydrous magnesium sulfate and filtered through silica gel.After concentrating the filtrate under reduced pressure, the residue wasdiluted with hexane (500 ml) and isopropyl ether (500 ml) and stirredunder ice cooling for 1 hr. The resulting crystalline precipitates werecollected by filtration, washed with cold hexane and then dried to givethe title compound (133.67 g) as pale yellow crystals (yield: 71.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.48(4H, t, J=6.2 Hz), 2.70(2H, m), 2.80(2H, m), 2.82(4H, t,J=6.2 Hz), 6.98(2H, t, J=8.8 Hz), 7.17(2H, dd, J=5.2, 8.8 Hz).(40-4) Methyl1-[2-(4-fluorophenyl)ethyl]-3-methyl-4-oxo-3-piperidinecarboxylate

Sodium salt (15.1 g) of methyl1-[2-(4-fluorophenyl)-ethyl]-4-oxo-3-piperidinecarboxylate was dissolvedin dimethylformamide (150 ml). Under ice cooling, methyl iodide (3.1 ml)was added thereto and the resultant mixture was stirred at roomtemperature overnight. Then ice water (500 ml) was added and theresultant mixture was extracted with ether (200 ml) twice. The organiclayer was washed with water (100 ml) and brine (100 ml), dried andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Fuji Silysia NH-DM2035, hexane/ethyl acetatesystem) to give the title compound (3.4 g) as a pale yellow liquid(yield: 23%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.26(3H, s), 2.16(1H, d, J=11.5 Hz), 2.45(2H, m), 2.66(2H, m),2.78(2H, m), 2.87(1H, m), 3.09(1H, m), 3.57(1H, dd, J=3.0 Hz, 11.5 Hz),3.70(3H, s), 6.97(2H, br-t), 7.17(2H, br-d).(40-5) 1-[2-(4-Fluorophenyl)ethyl]-3-methyl-4-piperidone

Conc. hydrochloric acid (12 ml) was added to a solution (12 ml) ofmethyl1-[2-(4-fluorophenyl)ethyl]-3-methyl-4-oxo-3-piperidinecarboxylate (3.4g) in toluene followed by heating under reflux for 2.5 hr. The reactionmixture was cooled and added under ice cooling to a 1.5 N aqueoussolution (100 ml) of sodium hydroxide. Further, the pH value of themixture was regulated to 9 with a 5 N aqueous solution of sodiumhydroxide. After extracting with ethyl acetate (100 ml) twice, theorganic layer was washed with water (100 ml) and brine (100 ml), driedand concentrated under reduced pressure to give the title compound (2.87g) as a pale yellow liquid (yield: 100%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.02(3H, d, J=7 Hz), 2.16(1H, t, J=10 Hz), 2.37(2H, m), 2.45(1H,m), 2.58(1H, m), 2.65(2H, m), 2.81(2H, t, J=7 Hz), 3.17(2H, m), 6.97(2H,br-t), 7.16(2H, br-d).

Production Example 41 Synthesis of 1-fluorophenethyl-4-formylpiperidine

(41-1) 1-Fluorophenethyl-4-methoxylidenepiperidine

Methoxymethyltriphenylphosphonium chloride (36.3 g) was suspended intetrahydrofuran (105 ml) and ice cooled. To the resultant suspensionwere successively added potassium t-butoxide (11.9 g) and1-fluorophenethyl-4-piperidone (7.8 g) dissolved in tetrahydrofuran (105ml) and the resultant mixture was stirred at room temperature. Afteradding water and ethyl acetate to the reaction solution, the layers wereseparated and the organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound (7.41 g) as a yellow oil(yield: 84.2%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.12(2H, t, J=5.6 Hz), 2.36(2H, t, J=5.6 Hz), 2.49(4H, m),2.57(4H, m), 2.79(4H, m), 3.55(3H, m), 5.81(1H, d, J=1.2 Hz), 6.96(2H,t, J=8.8 Hz), 7.15(2H, dd, J=5.6, 8.8 Hz).(41-2) 1-Fluorophenethyl-4-formylpiperidine

1-Fluorophenethyl-4-methylidenepiperidine (1.0 g) was dissolved in 1 Nhydrochloric acid followed by stirring at 70° C. for 4 hr. Afterallowing to cool, the solution was neutralized with a 5 N aqueoussolution of sodium hydroxide, extracted with ethyl acetate, washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the title compound (0.240 g) as a pale yellowoil (yield: 25.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.72-1.82(2H, m), 1.95-2.01(2H, m), 2.23-2.34(3H, m),2.59-2.63(2H, m), 2.90-2.95(2H, m), 6.96(2H, t, J=8.4 Hz), 7.15(2H, dd,J=5.6, 8.4 Hz).Production Example 42 Synthesis of1-(4-fluorophenethyyl)-4-piperidineethanol

4-Piperidineethanol (3.2 g) and 4-fluorophenethyl bromide (5.0 g) weretreated as in Example 2 to give the title compound (4.1 g) as acolorless oil (yield: 65%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.22-1.38(2H, m), 1.40-1.60(3H, m), 1.70-1.79(2H, m),1.91-2.02(3H, m), 2.50-2.59(2H, m), 2.78-2.81(2H, m), 2.95-3.01(2H, m),3.69-3.75(2H, m), 6.91-7.00(2H, m), 7.10-7.20(2H, m).Production Example 43 Synthesis of1-(4-fluorophenethyl)-4-piperidinacetaldehyde

A suspension of 1-(4-fluorophenethyl)-4-piperidine-ethanol (1.0 g),pyridinium chlorochromate (2.6 g) and molecular sieve (2.0 g) inmethylene chloride (60 ml) was stirred at room temperature for 1 hr.Then the reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (methanol/ethyl acetate system) to give the titlecompound (360 mg) (yield: 36%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.29-1.43(2H, m), 1.69-1.80(2H, m), 1.81-2.10(3H, m),2.33-2.42(2H, m), 2.50-2.60(2H, m), 2.72-2.80(2H, m), 2.93-3.00(2H, m),6.93-7.00(2H, m), 7.10-7.20(2H, m), 9.78-9.80(1H, m).Production Example 44 Synthesis of1-(4-fluorophenethyl)-4-aminopiperidine

A suspension of 1-(4-fluorophenethyl)-4-piperidone (5.0 g),hydroxylammonium chloride (1.9 g) and anhydrous sodium acetate (4.4 g)in ethanol (50 ml) was heated under reflux for 30 min. The reactionsolution was then concentrated under reduced pressure, diluted with asaturated aqueous solution of sodium bicarbonate and ethyl acetate andthe layers were separated. The organic layer was washed with brine anddried over magnesium sulfate. After evaporating the solvent, the residuewas diluted with tetrahydrofuran (50 ml) and lithium aluminum hydride(1.7 g) was added thereto in portions under ice cooling and stirringfollowed by heating under reflux for 4 hr. Under cooling with i cewater, water (1.7 ml), a 5 N aqueous solution of sodium hydroxide (5.1ml) and further water (1.7 ml) were carefully added to the reactionsolution in this order and the resultant mixture was stirred vigorously.The resulting precipitate was filtered off and the filtrate wasconcentrated under reduced pressure and purified by NH-silica gel columnchromatography (methylene chloride/methanol system) to give the titlecompound (4.0 g) as a pale yellow oil (yield: 80%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.31-1.60(4H, m), 1.80-1.89(2H, m), 2.01-2.11(2H, m),2.50-2.58(2H, m), 2.63-2.81(3H, m), 2.91-3.00(2H, m), 6.94-7.03(2H, m),7.14-7.25(2H, m).Production Example 45 Synthesis of 1-(piperidin-4-yl)-indoline

A mixture of indoline (25 g), 1-acetyl-4-piperidone (25 g), platinumoxide (0.5 g), acetic acid (20 ml) and ethanol (200 ml) wascatalytically reduced at ordinary temperature under atmospheric pressureovernight. After filtering off the catalyst, the filtrate wasconcentrated under reduced pressure and diluted with a 2 N aqueoussolution of sodium hydroxide and ethyl acetate. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate and purifiedby silica gel column chromatography (methylene chloride/ethanol system).To the obtained residue was added 5 N hydrochloric acid (300 ml)followed by heating the mixture under reflux for 2 hr. Then the reactionsolution was basified with a conc. aqueous solution of sodium hydroxide,diluted with ethyl acetate and the layers were separated. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to give the title compound (26 g) as brown crystals (yield:61%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.51-1.69(3H, m), 1.80-1.85(2H, m), 2.66-2.72(2H, m), 2.91(2H, t,J=8 Hz), 3.11-3.22(2H, m), 3.39(2H, t, J=8 Hz), 3.40-3.52(1H, m),6.41(1H, d, J=8 Hz), 6.60(1H, d, J=8 Hz), 7.01-7.10(2H, m).Production Example 46 Synthesis of 1-(piperidin-4-yl)-6-fluoroindoline

1-Chloroethyl chloroformate (2.8 g) was added dropwise into a solutionof 1-(1-benzylpiperidin-4-yl)-6-fluoroindoline (2.0 g) in toluene (50ml) followed by heating the mixture under reflux for 2 hr. Then thereaction solution was concentrated under reduced pressure and methanolwas added thereto followed by heating under reflux again for 2 hr. Afterconcentrating under reduced pressure, a 5 N aqueous solution of sodiumhydroxide and chloroform were added thereto, the layers were separated.The organic layer was then washed with brine and dried over anhydrousmagnesium sulfate to give the title compound (1.0 g) as a brown oil(yield: 70%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.59-1.71(2H, m), 1.80-1.87(2H, m), 2.06(1H, br-s), 2.68-2.75(2H,m), 2.91(2H, t, J=8 Hz), 3.20-3.29(2H, m), 3.34-3.48(1H, m), 3.45(2H, t,J=8 Hz), 6.08(1H, d, J=8 Hz), 6.23(1H, t, J=8 Hz), 6.91(1H, t, J=8 Hz).

Production Example 47 Synthesis of 6-bromoindoline

(47-1) 6-Bromo-2-oxyindole

Under ice cooling, diethyl malonate (500 g) was added dropwise into asuspension of sodium hydride (125 g) in dimethyl sulfoxide (800 ml).After the solution became homogeneous, the resultant mixture was heatedto 100° C. and a solution of 2,5-dibromonitrobenzene (500 g) in dimethylsulfoxide (400 ml) was added dropwise thereinto followed by stirring theresultant mixture at 100° C. for 5 hr. Then the reaction solution wasdiluted with ice water (2 l), mixed with ethyl acetate (8 l), and thelayers were separated. The organic layer was washed successively withwater (2 l) four times and brine and dried over anhydrous magnesiumsulfate. After evaporating the solvent under reduced pressure, theresidue was diluted with ethanol (2.5 l) followed by the addition of tin(380 g). Under ice cooling, conc. hydrochloric acid (1.5 l) was addeddropwise into the reaction mixture. After the completion of theaddition, the resultant mixture was heated under reflux for 3 hr anddiluted with ice water (8 l). The resulting crystalline precipitateswere collected by filtration, washed with water and hexane, and airdried at 50° C. for 24 hr to give the title compound (321 g) (yield:84%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.51(2H, s), 7.06(1H, s), 7.10(1H, d, J=8 Hz), 7.17(1H, d, J=8Hz), 8.27(1H, br-s).(47-2) 6-Bromoindoline

Under ice cooling, a borane/methyl sulfide complex (300 ml) was addeddropwise into a suspension of 6-bromo-2-oxyindole (311 g) in toluene (1l). Then the resultant mixture was slowly heated under reflux. After 2hr, it was ice cooled followed by the addition thereto of a 5 N aqueoussolution of sodium hydroxide (500 ml), an 8 N aqueous solution of sodiumhydroxide (500 ml) and ethyl acetate (400 ml). After vigorously stirringfor 1 hr, it was diluted with ethyl acetate (1.6 l) and water (1 l) andthe layers were separated. The organic layer was washed successivelywith water (1 l) twice and brine (0.5 l) and dried over anhydrousmagnesium sulfate. The residue was purified by NH-silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(169 g) (yield: 58%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.96(2H, t, J=8 Hz), 3.58(2H, t, J=8 Hz), 6.76(1H, s), 6.80(1H,d, J=8 Hz), 6.95(1H, d, J=8 Hz).Production Example 48 Synthesis of 1-(piperidin-4-yl)-6-bromoindoline

1-Chloroethyl chloroformate (13.7 g) was added dropwise into a solutionof 1-(1-benzylpiperidin-4-yl)-bromoindoline (14.3 g) in toluene (250 ml)and the resultant mixture was heated under reflux for 2 hr. Then it wasconcentrated under reduced pressure and methanol was added theretofollowed by heating under reflux for 2 hr. After concentrating underreduced pressure, a 5 N aqueous solution of sodium hydroxide and ethylacetate were added thereto and the layers were separated. The organiclayer was washed with brine and dried over anhydrous magnesium sulfateto give the title compound (8.4 g) as a brown oil (yield: 78%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.51-1.69(2H,m), 1.78-1.83(2H,m), 2.06(1H, br-s), 2.67-2.73(2H,m), 2.90(2H, t, J=8 Hz), 3.19-3.23(2H, m), 3.31-3.43(1H, m), 3.41(2H, t,J=8 Hz), 6.49(1H, s), 6.68(1H, t, J=8 Hz), 6.85(1H, t, J=8 Hz).Production Example 49 Synthesis of 1-(piperidin-4-yl)-6-nitroindoline

70% nitric acid (2.6 ml) was added dropwise at −15° C. into a solutionof 1-(piperidin-4-yl)indoline (6.9 g) in conc. sulfuric acid (50 ml).After 20 min, the reaction mixture was diluted with ice water andbasified with a conc. aqueous solution of sodium hydroxide, the reactionsolution was mixed with ethyl acetate, and the layers were separated.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give the titlecompound (7 g) as a brown oil (yield: 83%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.53-1.69(3H, m), 1.75-1.83(2H, m), 2.69-2.78(2H, m), 3.03(2H, t,J=8 Hz), 3.16-3.23(2H, m), 3.44-3.51(1H, m), 3.52(2H, t, J=8 Hz),7.08(1H, d, J=8 Hz), 7.10(1H, s), 7.48(1H, d, J=8 Hz).

Production Example 50 Synthesis of 6-dimethylaminoindoline

(50-1) 1-Acetyl-6-aminoindoline

Fuming nitric acid (11 ml) was added dropwise at −15° C. into a solutionof indoline (26.5 g) in con. sulfuric acid (250 ml). After 20 min, theresultant mixture was diluted with ice water and washed with ethylacetate. The aqueous phase was basified with a conc. aqueous solution ofsodium hydroxide, extracted with ethyl acetate, washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. To the residue were added acetic anhydride (100 ml) andpyridine (100 ml) and the reaction mixture was stirred at roomtemperature for 4 hr. After adding ice water to the reaction solution,the resulting crystalline precipitates were collected by filtration andmixed with an iron powder (40 g), ammonium chloride (60 g), water (70ml) and ethanol (300 ml). The resultant mixture was stirred at 60° C.overnight followed by filtration and concentration under reducedpressure. After adding water, the resultant mixture was stirredvigorously. The resulting crystalline precipitates were collected byfiltration and air dried at 70° C. overnight to give the title compound(19 g) as a brown powder (yield: 57%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.20(3H, s), 3.08(2H, t, J=8 Hz), 3.63(2H, br-s), 4.01(2H, t, J=8Hz), 6.33(1H, d, J=8 Hz), 6.91(1H, d, J=8 Hz), 7.67(1H, s).(50-2) 6-Dimethylaminoindoline

A mixture of 1-acetyl-6-aminoindoline (1.0 g), 37% formaldehyde (5.2 g),acetic acid (1.0 ml), platinum oxide (0.1 g) and methanol (20 ml) wascatalytically reduced at ordinary temperature under atmosphericpressure. After a day, the catalyst was filtered off and the filtratewas concentrated under reduced pressure. The residue was diluted with asaturated aqueous solution of sodium bicarbonate and ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate, concentrated under reduced pressure and purified by silica gelcolumn chromatography (methylene chloride/ethanol system). To theobtained residue was added 5 N hydrochloric acid (30 ml) followed byheating the resultant mixture under reflux for 1 hr. Then the reactionsolution was basified with a conc. aqueous solution of sodium hydroxideand extracted with chloroform. After purifying by silica gel columnchromatography (hexane/ethyl acetate system), the title compound (0.6 g)was obtained as a brown powder (yield: 65%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.89(6H, s), 2.91(2H, t, J=8 Hz), 3.52(2H, t, J=8 Hz), 3.70(1H,br-s), 6.11(1H, d, J=8 Hz), 6.12(1H, s), 6.95(1H, d, J=8 Hz).Production Example 51 Synthesis of 1-(piperidin-4-yl)-6-methoxyindoline

1-Chloroethyl chloroformate (10.5 g) was added dropwise into a solutionof 1-(1-benzylpiperidin-4-yl)-6-methoxyindoline (7.9 g) in toluene (200ml) and the resultant mixture was heated under reflux for 3 hr. Then itwas concentrated under reduced pressure and methanol was added theretofollowed by heating the resultant mixture under reflux for 2 hr. Afterconcentrating under reduced pressure, a 5 N aqueous solution of sodiumhydroxide and chloroform were added thereto, and the layers wereseparated. The organic layer was washed with brine and dried overanhydrous magnesium sulfate to give the title compound (4.1 g) as abrown oil (yield: 72%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.51-1.62(2H, m), 1.78-1.85(2H,m), 1.92(1H, br-s), 2.62-2.74(2H,m), 2.89(2H, t, J=8 Hz), 3.13-3.22(2H, m), 3.34-3.46(1H, m), 3.40(2H, t,J=8 Hz), 3.76(3H, s), 6.00(1H, s), 6.11(1H, d, J=8 Hz), 6.93(1H, d, J=8Hz).Production Example 52 Synthesis of1-(piperidin-4-yl)-6-acetamidomethylindoline

Under ice cooling, acetyl chloride (1.7 ml) was added dropwise into asolution of1-[1-(4-t-butoxycarbonyl)piperidin-4-yl]-6-aminomethylindoline (8.3 g)and triethylamine (2.4 g) in acetonitrile (150 ml) followed by stirringthe resultant mixture at room temperature for 1 hr. To the liquidreaction mixture were added a saturated aqueous solution of sodiumbicarbonate and ethyl acetate and the layers were separated. The organiclayer was then washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. After adding chloroform (100ml) and trifluoroacetic acid (50 ml), the resultant mixture was stirredat room temperature for 2 hr. After concentrating under reducedpressure, a 2 N aqueous solution of sodium hydroxide (100 ml) andtoluene (50 ml) were added thereto followed by vigorous stirring. Thenthe resultant mixture was purified by NH-silica gel columnchromatography (methanol/ethyl acetate system) to give the titlecompound (3.78 g) as white needles (yield: 58%).

m.p.: 165-167° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.64-1.86(4H, m), 2.52-2.82(2H, m), 2.93(2H, t, J=8 Hz),3.24-3.32(2H,m), 3.42(2H, t, J=8 Hz), 3.44-3.52(1H, m), 4.33(2H, d, J=5Hz), 5.67(1H, br-s), 6.34(1H, s), 6.51(1H, d, J=8 Hz), 7.00(1H, d, J=8Hz).

FAB-Mass: 274(MH⁺)

Production Example 53 Synthesis of 6-(N-methylsulfamoyl-methyl)indoline

(53-1) 1-t-butoxycarbonyl-6-bromoindoline

Di-t-butyl carbonate (6.7 g) was added to a solution of 6-bromoindoline(5.1 g) and triethylamine (3.1 g) in tetrahydrofuran (50 ml) followed bystirring the resultant mixture at room temperature overnight. Afteradding water and ethyl acetate thereto, the layers were separated andthe organic layer was washed with brine and dried over anhydrousmagnesium sulfate. The residue was then purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(5.5 g) as a colorless oil (yield: 71%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.56(9H, s), 3.04(2H, t, J=8 Hz), 3.99(2H, t, J=8 Hz), 6.98(1H,d, J=8 Hz), 7.03(1H, d, J=8 Hz), 8.04(1H, s).(53-2) 1-t-Butoxycarbonyl-6-hydroxymethylindoline

A 2.5 M solution (7 ml) of n-butyllithium in hexane was added dropwiseat −78° C. into a solution of 1-t-butoxycarbonyl-6-bromoindoline (3.5 g)in tetrahydrofuran (100 ml) over 5 min. After 10 min, dimethylformamide(1.4 ml) was added thereto and the resultant mixture was heated to roomtemperature. After adding a saturated aqueous solution of ammoniumchloride and ethyl acetate thereto, the layers were separated and theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. Then ethanol (20 ml)and sodium borohydride (0.4 g) were added to the residue followed bystirring the resultant mixture at room temperature for 1 hr. Afteradding ice water and ethyl acetate to the reaction solution, the organiclayer was separated, washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (1.9 g) as a colorless oil (yield:66%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.60(9H, s), 3.08(2H, t, J=8 Hz), 3.99(2H, t, J=8 Hz), 4.68(2H,s), 6.95(1H, d, J=8 Hz), 7.12(1H, d, J=8 Hz), 7.87(1H, s).(53-3) 1-Acetyl-6-chloromethylindoline

A solution of 1-t-butoxycarbonyl-6-hydroxymethyl-indoline (1.9 g) incon. hydrochloric acid (20 ml) was stirred at 50° C. overnight. Then itwas basified by adding a con. aqueous solution of sodium hydroxide.After adding ethyl acetate (40 ml) and acetyl chloride (0.5 ml), theresultant mixture was stirred at room temperature for 1 hr. The organiclayer was separated, washed with brine and dried over anhydrousmagnesium sulfate. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(0.87 g) as a colorless oil (yield: 54%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.23(3H, s), 3.20(2H, t, J=8 Hz), 4.09(2H, t, J=8 Hz), 4.59(2H,s), 7.06(1H, d, J=8 Hz), 7.16(1H, d, J=8 Hz), 8.25(1H, s).(53-4) 6-(N-Methylsulfamoylmethyl)indoline

A solution of 1-acetyl-6-chloromethylindoline (470 mg), sodium sulfite(330 mg) and tricaprylylmethylammonium chloride (50 mg) in water (30 ml)was heated under reflux for 1 hr and then concentrated under reducedpressure. To the residue were added phosphorus pentaoxide (500 mg) andphosphorus oxychloride (5 ml) followed by stirring the resultant mixtureat room temperature for 3 hr. Next, ice water and ethyl acetate wereadded to the reaction solution, the layers were separated. The organiclayer was washed with brine and dried over anhydrous magnesium sulfate.After concentratingunderreducedpressure, a 2 M solution of methylaminein tetrahydrofuran (20 ml) was added to the residue followed by stirringthe mixture at room temperature overnight. After adding a saturatedaqueous solution of sodium bicarbonate and ethyl acetate to the reactionsolution, the layers were separated and the organic layer was washedwith brine and dried over anhydrous magnesium sulfate. Afterconcentrating under reduced pressure, the crystalline precipitates werecollected, washed with ethanol and dissolved in 5 N hydrochloric acid (5ml) followed by heating under reflux for 1 hr. Under ice cooling, the pHvalue of the reaction solution was adjusted to pH 8 with a conc. aqueoussolution of sodium hydroxide, chloroform was added and the layers wereseparated. Then the organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive the title compound (100 mg) as white crystals (yield: 20%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.71(3H, s), 3.01(2H, t, J=8 Hz), 3.20(1H, br-s), 3.58(2H, t, J=8Hz), 4.15(2H, s), 4.25(1H, br-s), 6.65-6.69(2H, m), 7.08(1H, d, J=8 Hz).Production Example 54 Synthesis of 3-methylindoline

3-Methylindole (1.0 g) was dissolved in trifluoroacetic acid (30 ml).Under ice cooling, triethylsilane (2.4 ml) was added dropwise thereintofollowed by stirring for 1 hr. After concentrating under reducedpressure, a saturated aqueous solution of sodium bicarbonate and ethylacetate were added thereto, the layers were separated. Next, the organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate system) to give thetitle compound (0.673 g) as a pale yellow oil (yield: 66.3%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.32(3H, d, J=6.8 Hz), 3.11(1H, t, J=8.6 Hz), 3.36(1H, m),3.70(1H, t, J=8.6 Hz), 6.65(1H, d, J=8.0 Hz), 6.73(1H, t, J=8.0 Hz),7.03(1H, t, J=8.0 Hz), 7.09(1H, d, J=8.0 Hz).

Production Example 55 Synthesis of 3-(4-fluorophenyl)-indoline

(55-1) 2-(t-Butoxy)carbonylaminobenzyl alcohol

2-Aminobenzyl alcohol (5 g) was treated as reported in Synthesis, 871(1991). to give the title compound (5.776 g) as a pale yellow oil(yield: 60.4%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.52(9H, s), 4.69(2H, s), 7.02(1H, t, J=8.0 Hz), 7.17(1H, d,J=8.0 Hz), 7.31(1H, t, J=8.0 Hz), 7.63(1H, m), 7.91(1H, d, J=8.0 Hz).(55-2) 2-(t-Butoxy)carbonylaminobenzyl bromide

To 2-(t-butoxy)carbonylaminobenzyl alcohol (4.93 g) was addedtriethylamine (0.58 ml) followed by the same reaction as the onedescribed in the above Production Example 1. Then the reaction solutionwas concentrated under reduced pressure and purified by silica gelcolumn chromatography (hexane/ethyl acetate system) to give the titlecompound (5.380 g) as pale yellow crystals (yield: 86.1%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.58(9H, s), 4.51(2H, s), 6.68(1H, m), 7.06(1H, t, J=8.0 Hz),7.28(1H, d, J=8.0 Hz), 7.34(1H, t, J=8.0 Hz), 7.84(1H, d, J=8.0 Hz).(55-3) 2-(4-Fluorobenzyl)-N-(t-butoxy)carbonylaniline

2-(t-Butoxy)carbonylaminobenzyl bromide (2.98 g) and 4-phenylmagnesiumbromide were treated as reported in J. Organomet. C. 329, 133-138(1987). to give the title compound (1.187 g) as pale yellow crystals(yield: 39.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.46(9H, s), 3.93(2H,s), 6.12(1H,m), 6.91-7.12(7H, m), 7.82(1H,br-d).(55-4) 1-(t-Butoxy)carbonyl-3-(4-fluorophenyl)indole

2-(4-Fluorobenzyl)-N-(t-butoxy)carbonylaniline (0.5 g) was treated asreported in Synthesis, 871 (1991). to give the title compound (0.340 g)as a pale yellow oil (yield: 68.2%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.69(9H, s), 7.15(2H, t, J=8.8 Hz), 7.29(1H, t, J=8.0 Hz),7.37(1H, t, J=8.0 Hz), 7.59(2H, dd, J=6.0, 8.8 Hz), 7.67(1H, s),7.75(1H, d, J=8.0 Hz), 8.22(1H, d, J=8.0 Hz).(55-5) 3-(4-Fluorophenyl)indoline

1-(t-Butoxy)carbonyl-3-(4-fluorophenyl)indole (0.340 g) was freed fromthe protecting group with the use of trifluoroacetic acid and thentreated as in the above Production Example 54 to give the title compound(0.184 g) as a pale yellow oil (yield: 79.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.45(1H, t, J=8.8 Hz), 3.92(1H,t, J=8.8 Hz), 4.48(1H, t, J=8.8Hz), 6.72(2H, m), 6.89(1H, d, J=8.4 Hz), 6.99(2H, t, J=8.4 Hz), 7.08(1H,t, J=8.4 Hz), 7.23(2H, m).

Production Example 56 Synthesis of 3-(4-fluorobenzyl) indoline

(56-1) 3-(4-Fluorobenzyl)indole

3-Formylindole was treated as reported in Tetrahedron Lett., 1869(1986). to give the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 4.05(2H, s), 6.84(1H, s), 6.93(2H, t, J=8.4 Hz), 7.06(1H, t,J=8.0 Hz), 7.15-7.19(3H, m), 7.46(1H, d, J=8.0 Hz), 7.97(1H, m).(56-2) 3-(4-Fluorobenzyl)indoline

3-(4-Fluorobenzyl)indole (2.119 g) was dissolved in trifluoroacetic acid(3.9 ml). Under ice cooling, a 1.0 M solution (18.7 ml) of aborane/tetrahydrofuran complex in tetrahydrofuran was dropped into theabove solution followed by stirring the resultant mixture at roomtemperature for 1 hr. After adding water, the reaction solution wasconcentrated under reduced pressure. Then ethanol (20 ml) and a 5 Naqueous solution (46 ml) of sodium hydroxide were added and theresultant mixture was stirred at room temperature for 1 hr. After addingethyl acetate (200 ml) thereto, the layers were separated and theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (1.163 g) as a yellow oil (yield:54.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.80(1H, dd, J=8.0, 13.6 Hz), 3.06(1H, dd, J=4.6, 13.6 Hz),3.26(1H, m), 3.55(2H, m), 6.48-6.71(2H, m), 6.92(1H, t, J=7.6 Hz),6.99(2H, t, J=8.8 Hz), 7.05(1H, t, J=7.6 Hz), 7.15(1H, dd, J=5.6, 8.8Hz).

Production Example 57 Synthesis of 3-(3-pyridylmethyl)-indoline

(57-1) 3-(3-Pyridylmethyl)indole

3-Bromopyridine was treated as reported in Tetrahedron Lett., 1869(1986). to give the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 4.11(2H, s), 6.92(1H, s), 7.09(1H, t, J=8.0 Hz), 7.18(2H, m),7.46(1H, d, J=8.0 Hz), 7.48(1H, d, J=8.0 Hz), 7.54(1H, d, J=8.0 Hz),8.33(1H, m), 8.45(1H, m), 8.60(H, m).(57-2) 3-(3-Pyridylmethyl)indoline

3-(3-Pyridylmethyl)indole (0.212 g) was treated as in the aboveProduction Example 56-2 to give the title compound (0.253 g) as a yellowoil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.83(1H, m), 3.06(1H, m), 3.27(1H, d, J=3.2 Hz), 3.56(2H, m),6.50(1H, d, J=8.0 Hz), 6.69(1H, t, J=8.0 Hz), 6.92(1H, d, J=8.0 Hz),7.23(1H, m), 7.49(1H, d, J=8.0 Hz), 8.48(1H, m).

Production Example 58 Synthesis of 3-(4-methoxybenzyl)-indoline

(58-1) 3-(4-Methoxybenzyl)indole

1-Diethylcarbamoyl-3-formylindole (7.33 g), which had been obtainedaccording to the method of Tetrahedron Lett., 1869 (1986)., and4-methoxyphenylmagnesium bromide were treated as reported in TetrahedronLett., 1869 (1986). to give the title compound (5.480 g) as a paleyellow oil (yield: 77.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.78(3H, s), 4.06(2H, s), 6.82(2H, d, J=6.8 Hz), 6.90(1H, s),7.07(1H, t, J=8.0 Hz), 7.18(1H, t, J=8.0 Hz), 7.20(2H, d, J=6.8 Hz),7.36(1H, d, J=8.0 Hz), 7.51(1H, d, J=8.0 Hz), 7.89(1H, m).(58-2) 3-(4-Methoxybenzyl)indoline

3-(4-Methoxybenzyl)indole (0.5 g) was treated as in Production Example54 to give the title compound (0.332 g) as a pale yellow oil (yield:65.7%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.76(1H, dd, J=8.4, 14.0 Hz), 3.04(1H, dd, J=5.2, 14.0 Hz),3.54(2H, m), 3.76(1H, d, J=5.2 Hz), 3.81(3H, s), 6.65(1H, d, J=7.6 Hz),6.69(1H, t, J=7.6 Hz), 6.85(2H, d, J=8.2 Hz), 6.95(1H, d, J=7.6 Hz),7.04(1H, t, J=7.6 Hz), 7.12(2H, d, J=8.2 Hz).

Production Example 59 Synthesis of 3-(3-methoxyphenethyl) indoline

(59-1) 1-Diethylcarbamoyl-3-[2-(3-methoxyphenyl)vinyl]indole

3-Methoxybenzyltriphenylphosphonium chloride (1.71 g) and1-diethylcarbamoyl-3-formylindole (1.71 g), which had been synthesizedaccording to the method of Tetrahedron Lett., 1869 (1986)., were reactedin tetrahydrofuran (5 ml) as in the above Production Example 41-1 togive the title compound (0.842 g) as a brown oil (yield: 59.1%).(59-2) 1-Diethylcarbamoyl-3-(3-methoxyphenethyl)indole

1-Diethylcarbamoyl-3-[2-(3-methoxyphenyl)vinyl]indole (0.842 g) wasdissolved in methanol (20 ml) and catalytically reduced with the use ofpalladium carbon at room temperature under atmospheric pressure for 1hr. After filtering off the catalyst, the filtrate was concentratedunder reduced pressure to give the title compound (0.864 g) as a brownoil (yield: quantitative).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.19(6H, t, J=7.2 Hz), 3.01(4H, m), 3.42(4H, q, J=7.2 Hz),3.78(3H, s), 6.72(2H, m), 6.79(1H, d, J=8.4 Hz), 6.95(1H, s), 7.18(2H,t, J=8.4 Hz), 7.27(1H, m), 7.57(1H, d, J=8.4 Hz), 7.63(1H, d, J=8.4 Hz).(59-3) 3-(3-Methoxyphenethyl)indole

1-Diethylcarbamoyl-3-(3-methoxyphenethyl)indole (0.864 g) wasdeprotected as reported in Tetrahedron Lett., 7911 (1993). to give thetitle compound (0.554 g) as a brown oil (yield: 91.1%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.00(2H, m), 3.08(2H, m), 3.78(3H, s), 6.75(2H, m), 6.82(1H, d,J=8.0 Hz), 6.93(1H, s), 7.12(1H, t, J=8.0 Hz), 7.19(2H, q, J=8.0 Hz),7.36(1H, d, J=8.0 Hz), 7.62(1H, d, J=8.0 Hz), 7.93(1H, m).(59-4) 3-(3-Methoxyphenethyl)indoline

3-(3-Methoxyphenethyl)indole (0.554 g) was treated as in the aboveProduction Example 56-2 to give the title compound (0.133 g) as a paleyellow oil (yield: 23.8%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.83(1H, m), 2.15(1H, m), 2.70(2H, t, J=8.0 Hz), 3.34(1H, m),3.71(2H, t, J=8.0 Hz), 3.80(3H, s), 6.64(1H, d, J=8.0 Hz), 6.75(3H, m),6.80(1H, d, J=8.0 Hz), 7.03(1H, t, J=8.0 Hz), 7.10(1H, d, J=8.0 Hz),7.20(1H, t, J=8.0 Hz).

Production Example 60 Synthesis of 3-(3-fluorophenethyl)-indoline

(60-1) 3-[2-(3-Fluorophenyl)vinyl]indole

3-Formylindole (1.0 g) and 3-fluorobenzylphosphonium chloride (2.8 g)were treated as in the above Production Example 41-1 to give the titlecompound (0.598 g) as colorless crystals (yield: 73.1%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 6.51(1H, d, J=12.0 Hz), 6.80(1H, d, J=12.0 Hz), 6.89(1H, m),7.06-7.37(7H, m), 7.47(1H, dd, J=0.4, 8.0 Hz), 8.04(1H, m).(60-2) 3-(3-Fluorophenethyl)indole

3-[2-(3-Fluorophenyl)vinyl]indole (0.598 g) was treated as in the aboveProduction Example 59-2 to give the title compound (0.541 g) as a brownoil (yield: 89.7%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.04(4H, m), 6.90(2H, m), 6.98(1H, d, J=8.0 Hz), 7.13(1H, dt,J=0.8, 8.0 Hz), 7.23(2H, m), 7.36(1H, d, J=8.0 Hz), 7.61(1H, dd, J=0.8,8.0 Hz), 7.89(1H, br-s).(60-3) 3-(3-Fluorophenethyl)indoline

3-(3-Fluorophenethyl)indole (0.541 g) was treated as in the aboveProduction Example 56-2 to give the title compound (0.582 g) as a brownoil (yield: quantitative).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.87(1H, m), 2.14(1H, m), 2.72(2H, t, J=8.0 Hz), 3.26(2H, t,J=8.0 Hz), 3.30(1H, m), 3.71(1H, t, J=8.0 Hz), 6.65(1H, d, J=8.0 Hz),6.73(1H, t, J=8.0 Hz), 6.88(2H, m), 7.03(1H, t, J=8.0 Hz), 7.13(1H, d,J=8.0 Hz), 7.23(1H, m).Production Example 61 Synthesis of 4-(4-fluorophenyl)-indoline

A mixture of 4-bromoindole (1.0 g), which had been synthesized accordingto the method of J. Org. Chem. (1986, Vol. 5, No. 26, p. 5106.),4-fluorophenylboronic acid (1.1 g),tetrakis(triphenylphosphine)palladium (0.24 g), a 10% aqueous solution(10 ml) of sodium carbonate and toluene (20 ml) was heated under refluxfor 4 hr. Then ethyl acetate was added to the reaction solution and thelayers were separated. The organic layer was washed with brine and driedover anhydrous magnesium sulfate. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate system). To the resultingresidue was added trifluoroacetic acid (10 ml) and a 1 M solution (6.8ml) of a borane/tetrahydrofuran complex in tetrahydrofuran followed bystirring the mixture at 0° C. for 1 hr. After adding water, theresultant mixture was concentrated under reduced pressure. Then ethanoland an aqueous solution of sodium hydroxide were added thereto and thereaction mixture was stirred for 30 min. After adding ethyl acetate tothe reaction solution, the layers were separated and the organic layerwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate system) to give thetitle compound (0.5 g) as a colorless oil (yield: 46%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.01(2H, t, J=8 Hz), 3.50(2H, t, J=8 Hz), 3.81(1H, br-s),6.61(1H, d, J=8 Hz), 6.72(1H, d, J=8 Hz), 7.02-7.10(3H, m),7.38-7.41(2H, m).Production Example 62 Synthesis of thiazolo[5.4-f]indoline

Bromine (2.5 ml) was added dropwise into a solution of1-acetyl-6-aminoindoline (6.0 g) and potassium thiocyanate (9.3 g) inacetic acid (100 ml) followed by stirring the resultant mixture at roomtemperature for 5 hr. Under ice cooling, a 5 N aqueous solution ofsodium hydroxide was added thereto and the crystalline precipitates werecollected by filtration. Then these crystals were air dried at 60° C.overnight and dissolved in dimethylformamide (90 ml). After addingisoamyl nitrite (18 ml) dropwise thereinto, the reaction mixture wasstirred at 80° C. for 1 hr followed by concentration under reducedpressure. Then a 5 N aqueous solution of sodium hydroxide and chloroformwere added thereto and the layers were separated. The organic layerwashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified byNH-silica gel column chromatography (hexane/ethyl acetate system). Afteradding 5 N hydrochloric acid (150 ml), the mixture was heated underreflux for 30 min. Then a 5 N aqueous solution of sodium hydroxide andethyl acetate were added thereto and the layers were separated. Theorganic layer was washed with brine and dried over anhydrous magnesiumsulfate. The residue was purified by silica gel column chromatography(hexane/ethyl acetate system) to give the title compound (1.2 g) asbrown powdery crystals (yield: 21%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.14(2H, t, J=8 Hz), 3.65(2H, t, J=8 Hz), 4.00(1H, br-s),7.28(1H, s), 7.58(1H, s), 8.83(1H, s).Production Example 63 Synthesis of6-(4-fluorobenzene-sulfonylamino)indoline

Under ice cooling, 4-fluorobenzenesulfonyl chloride (1.4 g) was addeddropwise into a solution (10 ml) of 1-acetyl-6-aminoindoline (1.0 g) inpyridine followed by stirring the resultant mixture for 30 min. Afterconcentrating it under reduced pressure, 5 N hydrochloric acid was addedthereto and the resultant mixture was heated under reflux for 5 hr. Thenthe reaction solution was basified with a conc. aqueous solution ofsodium hydroxide and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate and purifiedby NH-silica gel column chromatography (methylene chloride/ethanolsystem) to give the title compound (1.36 g) as white powdery crystals(yield: 82%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.95(2H, t, J=8 Hz), 3.64(2H, t, J=8 Hz), 3.78(1H, br-s),6.22(1H,d, J=8 Hz), 6.33(1H, br-s), 6.48(1H, s), 6.90(1H, d, J=8 Hz),7.08-7.12(2H, m), 7.71-7.80(2H, m).Production Example 64 Synthesis of 4-methoxyindoline

Under ice cooling, a 1 M solution (6.2 ml) of a borane/tetrahydrofurancomplex in tetrahydrofuran was added dropwise into a solution of4-methoxyindole (0.46 g) in trifluoroacetic acid (10 ml) followed bystirring the resultant mixture for 1 hr.

After adding water, the resultant mixture was concentrated under reducedpressure and ethanol and a 5 N aqueous solution of sodium hydroxide wereadded thereto followed by stirring the mixture overnight. Afterconcentrating it under reduced pressure, the residue was extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound (130 mg) as a brown oil(yield: 28%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.95(2H, t, J=8 Hz), 3.52(2H, t, J=8 Hz), 3.80(1H, s), 6.28(1H,d, J=8 Hz), 6.30(1H, d, J=8 Hz), 6.99(1H, t, J=8 Hz).

Production Example 65 Synthesis of 1-(piperidin-4-yl)indan

(65-1) 1-Hydroxy-1-(4-pyridyl)indan

To 4-bromopyridine hydrochloride (19.4 g) were added a 2 N aqueoussolution (120 ml) of sodium hydroxide and ether (300 ml) to extract4-bromopyridine. Then the ether layer was dried over anhydrous potassiumcarbonate and cooled to −70° C. Into the resultant mixture was addeddropwise 2.5 M n-butyllithium (40 ml) with stirring. After thecompletion of the addition, the reaction solution was stirred for 30 minand a solution (60 ml) of 1-indanone in ether was added thereto at −70°C. Then the reaction solution was allowed to warm to room temperatureover 12 hr. Then it was pertitioned between ethyl acetate and asaturated aqueous solution of ammonium chloride. The ethyl acetate layerwas washed with water, dried and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate system) to give the title compound (7.6 g) as acolorless oil (yield: 35.9%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.40-2.50(2H, m), 2.82(1H, br-s), 2.94-3.04(1H, m) 3.17-3.26(1H,m), 7.02(1H, d, J=8.4 Hz), 7.22(1H, dt, J=8.4, 2.8 Hz), 7.33(2H, d,J=8.0 Hz), 7.30-7.37(2H, m), 8.47(2H, d, J=8.0 Hz).(65-2) 1-(Piperdin-4-yl)indan

A mixture of 1-hydroxy-1-(4-pyridyl)indan (6.0 g), 6 N hydrochloric acid(20 ml) and ethanol (20 ml) was heated to 100° C for 30 min. Then thereaction solution was concentrated under reduced pressure and ethanol(200 ml) and platinum oxide (0.2 g) were added to the residue followedby hydrogenation under 3 kg/cm². After the completion of the reaction,the reaction solution was filtered through celite and extracted withethanol. The filtrate was concentrated under reduced pressure and theresidue was partitioned between ethyl acetate and a 2 N aqueous solutionof sodium hydroxide. The ethyl acetate layer was washed with water,dried, concentrated under reduced pressure and purified by NH-silica gelcolumn chromatography (ethyl acetate) to give the title compound (4.2 g)as pale brown powdery crystals (yield: 73.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.13-1.49(3H, m), 1.51(1H, br-s), 1.62-1.70(1H, m), 1.72-1.82(1H,m), 1.90-2.00(1H, m), 2.02-2.18(1H, m), 2.50-2.64(2H, m), 2.75-2.92(2H,m), 3.01-3.13(3H, m), 7.09-7.21(4H, m).Production Example 66 Synthesis of1-(piperidin-4-yl)-6-chloro-7-azaindoline

A mixture of 2,6-dichloro-3-formylmethylpyridine (5.6 g), ethyl4-amino-1-piperidinecarboxylate (7.6 g), platinum oxide (140 mg), aceticacid (1.0 ml) and ethanol (100 ml) was catalytically reduced at ordinarytemperature under atmospheric pressure in a stream of hydrogen. After 6hr, the catalyst was filtered off and the filtrate was concentratedunder reduced pressure. The residue was diluted with a saturated aqueoussolution of sodium bicarbonate and ethyl acetate and the layers wereseparated. The organic layer was washed with brine and dried overmagnesium sulfate and then the solvent was distilled off. The residuewas purified by silica gel column chromatography (methylene chloride/ethanol system). After adding triethylamine (1.5 g) ando-dichlorobenzene (100 ml), the resultant mixture was heated at 180° C.for 2 hr. Then the reaction solution was concentrated under reducedpressure and diluted with a saturated aqueous solution of sodiumhydrogencarbonate and ethyl acetate and the layers were separated. Theorganic layer was washed with brine, dried over magnesium sulfate andpurified by silica gel column chromatography (hexane/ethyl acetatesystem). After adding potassium hydroxide (10 g) and ethylene glycol(200 ml) to the residue, the resultant mixture was heated under refluxfor 2 hr. Then the reaction solution was diluted with water and ethylacetate and the layers were separated. The organic layer was washed withbrine and dried over magnesium sulfate. After evaporating the solventthe title compound (2.3 g) was obtained as a brown oil (yield: 33%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.71-1.89(4H, m), 2.80-2.91(2H, m), 2.94(2H, t, J=8 Hz),3.25-3.34(2H, m), 3.66(2H, t, J=8 Hz), 4.11-4.23(1H, m), 6.38(1H, d, J=8Hz), 7.04(1H, d, J=8 Hz).Production Example 67 Synthesis of1-(4-piperidinyl)-7-methoxy-1.2.3.4-tetrahydroquinoline

A solution of 1-(4-piperidinyl)-7-methoxy-3,4-dihydrocarbostyryl (1.50g), which had been obtained by the method described in JP-A 3-173870, inTHF (50 ml) was cooled to 0° C. and lithium aluminum hydride (660 mg)was added thereto in five portions. The reaction mixture was stirred at0° C. for 10 min and then heated under reflux for 4 hr. After thecompletion of the reaction, the reaction mixture was cooled to 0° C. andwater (0.66 ml), a 5 N aqueous solution (0.66 ml) of sodium hydroxideand further water (2 ml) were successively added thereto. After furtheradding magnesium sulfate, the resultant mixture was stirred for 10 min.The resulting precipitate was filtered off through celite and thefiltrate was concentrated to give the title compound (1.27 g) (yield:89%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.62-1.91(6H, m), 2.02-2.12(1H, m), 2.64-2.75(3H, m),3.07-3.22(4H, m), 3.51-3.74(1H, m), 3.77(3H, s), 6.13(1H, dt, J=8.0, 2.0Hz), 6.24(1H, t, J=2.0 Hz), 6.85(1H, d, J=8.0 Hz).

EXAMPLES

Example 1: Synthesis of 1-[1-(4-fluorophenyl)piperdine-4-yl]indoline

Triacetoxylated sodium borohydride (760 mg) was added to a mixture ofindoline (300 mg), 1-(4-fluorophenyl)-4-piperidone (580 mg), acetic acid(650 mg) and dichloroethane (30 ml), and the mixture was stirred for 2hr. The obtained reaction solution was mixed with ethyl acetate and asaturated aqueous solution of sodium bicarbonate and the layers wereseparated. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (470 mg) as white prismatic crystals(yield: 63%).

m.p.: 120-122° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.82-1.93(4H, m), 2.71-2.82(2H, m), 2.92-3.01(2H, m),3.39-3.43(3H, m), 3.63-3.71(2H, m), 6.42-6.49(1H, m), 6.60-6.65(1H, m),6.90-7.10(6H, m).

FAB-Mass: 297(MH+).

Example 2: Synthesis of 1-[1-(4-fluorobenzyl)piperidin-4-yl]indoline

4-Fluorobenzyl bromide (0.067 ml) was dissolved in N,N-dimethylformamide(2.5 ml). After adding 4-fluorobenzyl bromide (0.067 ml) andtriethylamine (0.075 ml), the resulting mixture was stirred for 5 hr.Then water and ethyl acetate were added thereto and the layers wereseparated. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (0.131 g) as colorless crystals(yield: 86.1%).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride of the titlecompound was obtained as colorless crystals.

m.p. (hydrochloride): 223° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.84(2H, br-d), 2.14(2H, m), 2.90(2H, t, J=8.4 Hz), 3.01(2H, m),3.33(2H, t, J=8.4 Hz), 3.40(2H, br-d), 3.72(1H, m), 4.27(2H, d, J=4.8Hz), 6.62(1H, d, J=7.6 Hz), 6.63(1H, t, J=7.6 Hz), 7.02(1H, t, J=7.6Hz), 7.06(1H, d, J=7.6 Hz), 7.31(2H, t, J=8.8 Hz), 7.70(2H, dd, J=5.6,8.8 Hz).

ESI-Mass: 311.1(MH+).

Example 3: Synthesis of 1-(1-phenethylpiperidin-4-yl)indoline

(2-Bromoethyl) benzene (0.19 g) was treated as in Example 2 to give thetitle compound (0.126 g) as a colorless oil (yield: 77.3%).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride of the titlecompound was obtained as colorless crystals.

m.p. (hydrochloride): 234° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.89(2H, m), 2.10(2H, m), 2.91(2H, t, J=8.2 Hz), 3.09(4H, m),3.26(2H, m), 3.35(2H, t, J=8.2 Hz), 3.65(2H, m), 3.76(1H, m), 6.60(1H,d, J=7.6 Hz), 6.61(1H, t, J=7.6 Hz), 7.02(1H, t, J=7.6 Hz), 7.06(1H, d,J=7.6 Hz), 7.28(3H, m), 7.35(2H, m).

FAB-Mass: 307(MH+).

Example 4: Synthesis of 1-[1-(4-bromophenethyl)piperidin-4-yl]indoline

4-Bromophenethyl bromide (0.1 g) was treated as in Example 2 to give thetitle compound (0.119 g) as a colorless oil (yield: 63.0%).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride (0.110 g) ofthe title compound was obtained.

m.p. (hydrochloride): 230° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.88(2H, br-d), 2.09(2H, m), 2.91(2H, t, J=8.2 Hz), 3.09(4H, m),3.25(2H,m), 3.36(2H, t, J=8.2 Hz), 3.62(2H, br-d), 3.75(1H, m), 6.59(1H,d, J=8.0 Hz), 6.60(1H, t, J=8.0 Hz), 7.02(1H, t, J=8.0 Hz), 7.05(1H, d,J=8.0 Hz), 7.27(2H, d, J=8.4 Hz), 7.55(2H, d, J=8.4 Hz).

FAB-Mass: 385(MH+).

Example 5: Synthesis of 1-[1-(3-chlorophenethyl)piperidin-4-yl]indoline

3-Chlorophenethyl bromide (0.1 g) was treated as in Example 2 to givethe title compound (0.119 g) as a colorless oil (yield: 63.0%).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride (0.110 g) ofthe title compound was obtained.

m.p. (hydrochloride): 219° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.89(2H, br-d), 2.11(2H, m), 2.91(2H, t, J=8.4 Hz), 3.09(4H, m),3.27(2H, m), 3.35(2H, t, J=8.4 Hz), 3.63(2H, br-d), 3.77(1H, br-t),6.62(2H, m), 7.02(1H, t, J=8 Hz), 7.06(1H, d, J=8 Hz), 7.27(1H, d, J=7.2Hz), 7.32-7.41(3H, m).

FAB-Mass: 341(MH+).

Example 6 Synthesis of 1-[1-(4-chlorophenethyl)piperidin-4-yl]indoline

4-Chlorophenethyl bromide (0.1 g) was treated as in Example 2 to givethe title compound (0.125 g) as a colorless oil (yield: 74.8%).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride (0.120 g) ofthe title compound was obtained.

m.p. (hydrochloride): 228° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.88(2H, br-d), 2.11(2H, m), 2.91(2H, t, J=8.4 Hz), 3.09(4H, m),3.25(2H, m), 3.35(2H, t, J=8.4 Hz), 3.63(2H, br-d), 3.77(1H, br-t),6.62(1H, d, J=8.0 Hz), 6.63(1H, t, J=8.0 Hz), 7.03(1H, t, J=8.0 Hz),7.06(1H, d, J=8.0 Hz), 7.33(2H, d, J=8.6 Hz), 7.42(2H, d, J=8.6 Hz).

FAB-Mass: 341 (MH+).

Example 7: Synthesis of 1-[1-(2-fluorophenethyl)piperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (300 mg) and 2-fluorophenethyl bromide (340mg) obtained in the same manner as the one of Production Example 1 weretreated as in Example 2 to give the hydrochloride (290 mg) of the titlecompound as a white powder (yield: 54%).

m.p. (hydrochloride): 229-231° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90(2H, m), 2.00-2.12(2H, m), 2.89(2H, t, J=8 Hz),3.01-3.16(4H, m), 3.20-3.30(2H, m), 3.33(2H, t, J=8 Hz), 3.60-3.79(3H,m), 6.53-6.60(2H, m), 6.96-7.04(2H, m) 7.16-7.23(2H, m), 7.29-7.40(2H,m), 10.80(1H, br-s).

FAB-Mass: 325(MH+).

Example 8: Synthesis of 1-[1-(3-fluorophenethyl)piperidin-4-yl]indoline

Dicyclohexylcarbodiimide (560 mg) was added to a solution of1-(piperidin-4-yl)indoline (500 mg) in methylene chloride (30 ml)followed by stirring at 0° C. After 1 hr, 3-fluorophenylacetic acid (420mg) was added thereto and the resultant mixture was stirred at roomtemperature for 2 hr. The crystalline precipitates were filtered off andthe filtrate was concentrated under reduced pressure and purified bysilica gel column chromatography (hexane/ethyl acetate system). Theresidue was diluted with tetrahydrofuran (30 ml). Next, lithium aluminumhydride (290 mg) was added in portions thereto under ice cooling andstirring and the resultant mixture was stirred at room temperatureovernight. Under ice cooling, water (0.29 ml), a 5 N aqueous solution(0.87 ml) of sodium hydroxide and further water (0.29 ml) were carefullyadded dropwise into the reaction solution followed by vigorous stirring.The resulting precipitate was filtered off and the filtrate wasconcentrated under reduced pressure and purified by silica gel columnchromatography (hexane/ethyl acetate system). Then the obtained productwas converted into a hydrochloride in a conventional manner to give thehydrochloride (550 mg) of the title compound as a white powder (yield:61%).

m.p. (hydrochloride): 231-234° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.89(2H, m), 1.93-2.07(2H, m), 2.88(2H, t, J=8 Hz),3.00-3.11(4H, m), 3.23-3.35(4H, m), 3.58-3.75(3H, m), 6.51-6.57(2H, m),6.95-7.03(2H, m), 7.06-7.19(2H, m), 7.35-7.41(2H, m).

FAB-Mass: 325(MH+).

Example 9: Synthesis of 1-[1-(4-fluorophenethyl)piperidin-4-yl]indoline

A 2.5 M solution (0.36 ml) of n-butyllithium in hexane was addeddropwise over 10 min into a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (300 mg) intetrahydrofuran (15 ml) at −78° C. After 10 min, the resultant mixturewas mixed with a saturated aqueous solution of ammonium chloride andethyl acetate and the layers were separated. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate and purifiedby silica gel column chromatography (methylene chloride/ethanol system).Then the obtained product was converted into the hydrochloride in aconventional manner to give the hydrochloride (240 mg) of the titlecompound as white needles (yield: 90%).

m.p. (hydrochloride): 233° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90(2H, m), 2.00-2.13(2H, m), 2.90(2H, t, J=8 Hz),3.00-3.14(4H, m), 3.19-3.28(2H, m), 3.30(2H, t, J=8 Hz), 3.58-3.63(2H,m), 3.69-3.79(1H, m), 6.51-6.60(2H, m), 6.94-7.08(2H, m), 7.12-7.20(2H,m), 7.29-7.39(2H, m), 10.70(1H, br-s).

FAB-Mass: 325(MH+).

Example 10: Synthesis of1-[1-(2,4-difluorophenethyl)-piperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (500 mg) and 2,4-difluorophenylacetic acid(470 mg) were treated as in Example 8 to give the hydrochloride (720 mg)of the title compound as a white powder (yield: 76%).

m.p. (hydrochloride): 226-227° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-2.08(4H, m), 2.89(2H, t, J=8 Hz), 3.00-3.15(4H, m),3.20-3.39(4H, m), 3.40-3.75(3H, m), 6.49-6.57(2H, m), 6.94-7.04(2H, m),7.07-7.12(1H, m), 7.23-7.30(1H, m), 7.39-7.46(1H, m).

FAB-Mass: 343(MH+).

Example 11: Synthesis of1-[1-(3,4-difluorophenethyl)-piperidin-4-yl]indoline

3,4-Difluorophenylacetic acid (0.095 g) was dissolved in tetrahydrofuran(5.0 ml). After adding 1,1-carbonyldiimidazole (0.089 g) to theresultant solution, the resultant mixture was stirred at roomtemperature for 15 min followedbytheadditionof1-(piperidin-4-yl)indoline (0.1 g). After stirring at room temperatureovernight, the resultant mixture was diluted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give a colorless oil.Then this product was dissolved in tetrahydrofuran (2.5 ml) and lithiumaluminum hydride (0.046 g) was added thereto under ice cooling followedby heating under reflux for 2 hr. After cooling the reaction solution,water (0.05 ml), a 5 N aqueous solution (0.05 ml) of sodium hydroxideand further water (0.15 ml) were added thereto. The precipitated solidwas filtered off and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate system) to give the title compound (0.190 g) as acolorless oil (yield: quantitative).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride (0.120 g) ofthe title compound was obtained.

m.p. (hydrochloride): 223° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.87(2H, br-d), 2.06(2H, m), 2.90(2H, t, J=8.4 Hz), 3.09(4H, m),3.28(2H, m), 3.33(2H, t, J=8.4 Hz), 3.62(2H, br-d), 3.74(1H, br-t),6.57(1H, d, J=7.0 Hz), 6.58(1H, t, J=7.0 Hz), 7.01(1H, t, J=7.0 Hz),7.04(1H, d, J=7.0 Hz), 7.16(1H, m), 7.39-7.46(2H, m).

FAB-Mass: 343(MH+).

Example 12: Synthesis of1-[1-(3,5-difluorophenethyl)-piperidin-4-yl]indoline

3,5-Difluorophenylacetic acid (0.189 g) was treated as in Example 11 togive the title compound (0.342 g) as a colorless oil (yield:quantitative).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride (0.268 g) ofthe title compound was obtained.

m.p. (hydrochloride): 208° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.89(2H, br-d), 2.12(2H, m), 2.92(2H, t, J=8.2 Hz), 3.09(4H, m),3.27(2H, m), 3.36(2H, t, J=8.2 Hz), 3.61(2H, br-d), 3.78(1H, m),6.64(1H, d, J=8.0 Hz), 6.64(1H, t, J=8.0 Hz), 7.04(1H, t, J=8.0 Hz),7.07(1H, d, J=8.0 Hz), 7.14-7.18(1H, m), 7.38-7.45(2H, m).

FAB-Mass: 343(MH+).

Example 13: Synthesis of1-[1-(4-fluorophenylpropyl)-piperidin-4-yl]indoline

Ethanol (50 ml) was added to 4-fluorocinnamic acid (5 g) and then ethylacetate was further added thereto to dissolve completely. After adding apalladium carbon catalyst, catalytic reduction was carreid out underatmospheric pressure. Then the reaction mixture was filtered throughcelite and the filtrate was concentrated under reduced pressure. Aportion (0.082 g) of the resulting colorless crystals was dissolved intetrahydrofuran (5.0 ml), and carbonyldiimidazole (0.079 g) and1-(4-piperidyl) indoline (0.1 g) were added thereto followed by stirringat room temperature for 14 hr. Then the reaction solution was dilutedwith ethyl acetate, washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give a pale yellowoily substance (0.171 g). This product was dissolved in tetrahydrofuran(5.0 ml) and lithium aluminum hydride (0.046 g) was added thereto underice cooling. After heating under reflux for 2 hr, the reaction mixturewas ice cooled again and water (0.05 ml), a 5 N aqueous solution (0.05ml) of sodium hydroxide and further water (0.15 ml) were added thereto.The resulting solid was filtered off and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(0.113 g) as a colorless oil (yield: 68.1%).

Next, hydrochloric acid-was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride (hygroscopic)of the title compound was obtained.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83(2H, br-d), 1.97-2.14(4H, m), 2.64(2H, t, J=8.0 Hz), 2.90(2H,t, J=8.0 Hz), 3.00(4H, m), 3.33(2H, t, J=8.4 Hz), 3.54(2H, br-d),3.73(1H, m), 6.58(1H, d, J=7.6 Hz), 6.61(1H, t, J=7.6 Hz), 7.02(1H, t,J=7.6 Hz), 7.05(1H, d, J=7.6 Hz), 7.14(2H, t, J=8.8 Hz), 7.29(2H, dd,J=5.6, 8.8 Hz).

ESI-Mass: 339.2(MH+).

Example 14: Synthesis of1-{1-[2-(4-fluorophenyl)propyl]piperidin-4-yl}indoline

1-(4-Piperazinyl)indoline (0.20 g) was dissolved in dimethylformamide (3ml) and 4-(2-bromo-1-methylethyl)fluorobenzene (10.0 g) andtriethylamine (0.14 ml) were added to the resultant solution followed bystirring at 60° C. overnight. After adding water, the liquid reactionmixture was extracted with ethyl acetate. The organic layer was washedwith brine and dried over magnesium sulfate. After evaporating thesolvent, the resulting residue was purified by NH-silica gel columnchromatography (methanol/methylene chloride system) to give the titlecompound (178 mg) as an oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.37(3H, d, J=6.8 Hz), 1.60-2.10(8H, m), 2.85-3.50(8H, m),6.36(1H, d, J=7.5 Hz), 6.58(1H, t, J=7.5 Hz), 6.97-7.07(4H, m),7.24-7.30(2H, m).

FAB-Mass: 339(MH+).

Example 15: Synthesis of1-[1-(4-fluorophenylbutyl)piperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (1.0 g) and 4-(4-fluorophenyl)butyric acid(0.9 g) were treated as in Example 8 to give the hydrochloride (0.23 g)of the title compound as a white powder (yield: 12%).

m.p. (hydrochloride): 204-206° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.51-1.71(4H, m), 1.79-1.86(2H, m), 1.89-2.02(2H, m), 2.60(2H, t,J=7 Hz), 2.87(2H, t, J=8 Hz), 2.92-3.07(4H, m), 3.29(2H, t, J=7 Hz),3.47-3.53(2H, m), 3.62-3.72(1H, m), 6.48-6.56(2H, m), 6.92-7.02(2H, m),7.06-7.12(2H, m), 7.20-7.28(2H, m), 9.99(1H, br-s).

FAB-Mass: 353(MH+).

Example 16: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]methylindoline

1-Fluorophenethyl-4-formylpiperidine (0.240 g) and indoline (0.095 ml)were dissolved in 1,2-dichloroethane (3.5 ml). After successively addingacetic acid (0.29 ml) and triacetoxylated sodium borohydride (0.36 g),the resultant mixture was stirred at room temperature for 2 hr. Then itwas mixed with a saturated aqueous solution of sodium bicarbonate andethyl acetate and the layers were separated. The organic layer waswashed with a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound (0.211 g) as a yellow oil(yield: 73.3%).

Next, oxalic acid (28 mg) was added to the product to give a saltfollowed by recrystallization from acetone. Thus, the oxalate of thetitle compound was obtained as colorless crystals.

m.p. (oxalate): 201-206° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.57(2H, m), 1.90(1H, m), 1.95(2H, m), 2.92(6H, m), 3.07(2H, m),3.23(2H, m), 3.34(2H, t, J=8.4 Hz), 3.57(2H, br-d), 6.52(1H, d, J=7.6Hz), 6.58(1H, t, J=7.6 Hz), 6.99(1H, t, J=7.6 Hz), 7.03(1H, d, J=7.6Hz), 7.18(2H, t, J=8.8 Hz), 7.33(2H, dd, J=5.2, 8.8 Hz).

ESI-Mass: 339.1(MH+).

Example 17: Synthesis of1-{2-[1-(4-fluorophenethyl)piperidin-4-yl]ethyl}indoline

Indoline (170 mg), 1-(4-fluorophenethyl)-4-piperidinacetaldehyde (360mg), acetic acid (440 mg) and triacetoxylated sodium borohydride (490mg) were treated as in Example 1 to give the hydrochloride (270 mg) ofthe title compound as white prisms (yield: 48%).

m.p. (hydrochloride): 159-161° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.45-1.70(5H, m), 1.89-1.98(2H, m), 2.80-3.10(8H, m),3.14-3.36(4H, m), 3.50-3.58(2H, m), 6.50-6.58(2H, m), 6.96-7.03(2H, m),7.16-7.21(2H, m), 7.30-7.38(2H, m), 10.16(1H, m).

FAB-Mass: 353(MH+).

Example 18: Synthesis of 1-[1-(4-methoxyphenethyl)piperdin-4-yl]indoline

4-Methoxyphenethyl bromide (0.23 g) was treated as in Example 2 to givethe title compound (0.131 g) as colorless crystals (yield: 86.1%).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride of the titlecompound was obtained as colorless crystals.

m.p. (hydrochloride): 244° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.88(2H, m), 2.02(2H, m), 2.90(2H, t, J=8.4 Hz), 3.00(2H, m),3.10(2H, m), 3.21(2H, m), 3.33(2H, t, J=8.4 Hz), 3.63(2H, br-d),3.73(3H, s), 3.74(1H, m), 6.57(1H, d, J=7.6 Hz), 6.59(1H, t, J=7.6 Hz),6.91(2H, d, J=8.4 Hz), 7.01(1H, t, J=7.6 Hz), 7.04(1H, d, J=7.6 Hz),7.21(2H, d, J=8.4 Hz).

FAB-Mass: 337(MH+).

Example 19: Synthesis of1-[1-(3-methoxyphenethyl)piperidin-4-yl]indoline

3-Methoxyphenethyl alcohol was treated as in Production Example 1. Thenthe pale yellow oily substance (0.23 g) thus obtained was treated as inExample 2 to give the title compound (0.150 g) as colorless crystals(yield: 45.4%).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride of the titlecompound was obtained as colorless crystals.

m.p. (hydrochloride): 229° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.88(2H, br-d), 2.14(2H, m), 2.92(2H, t, J=8.4 Hz), 3.07(4H, m),3.25(2H, m), 3.37(2H, t, J=8.4 Hz), 3.63(2H, br-d), 3.75(3H, s),3.77(1H, m), 6.57(1H, d, J=7.6 Hz), 6.45(1H, m), 6.81-6.88(3H, m),7.05(2H, m), 7.26(1H, d, J=8.0 Hz).

FAB-Mass: 337(MH+).

Example 20: Synthesis of1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline

1-[1-(4-Methoxyphenethyl)piperidin-4-yl]indoline (0.23 g) was dissolvedin a 47% aqueous solution (5 ml) of hydrobromic acid and the resultantsolution was heated under reflux for 90 min. After allowing to cool, theresultant mixture was poured into a saturated aqueous solution of sodiumbicarbonate (pH 9-10), extracted with ethyl acetate, washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by NH-silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(0.113 g) as colorless crystals (yield: 75.7%).

Next, hydrochloric acid was added to the product to give a salt followedby recrystallization from ethanol. Thus, the hydrochloride of the titlecompound was obtained as colorless crystals.

m.p. (hydrochloride): 240° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.87(2H, m), 2.09(2H, m), 2.91(2H, t, J=8.4 Hz), 2.95(2H, m),3.07(2H, m), 3.18(2H, m), 3.34(2H, t, J=8.4 Hz), 3.62(2H, br-d),3.75(1H, m), 6.61(2H, m), 6.73(2H, d, J=8.4 Hz), 7.05(4H, m), 10.69(1H,br-s).

FAB-Mass: 323(MH+).

Example 21: Synthesis of 1-[1-(4-cyanophenethyl)piperidin-4-yl]indoline

1-[1-(4-Hydroxyiminomethylphenethyl)piperidin-4-yl]indoline (0.466 g)was dissolved in methylene chloride (6.5 ml) and triethylamine (0.35 ml)was added thereto. In a nitrogen atmosphere at −78° C., trifluoroaceticanhydride (0.14 ml) was added dropwise into the resultant solutionfollowed by stirring for 3 hr. After adding a saturated aqueous solutionof sodium bicarbonate, the resultant mixture was extracted with ethylacetate, washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/methylene chloride/methanolsystem) to give the title compound (0.126 g) as a pale yellow oil(yield: 28.9%).

Next, hydrochloric acid was added to the product to give a salt. Thus,the hydrochloride of the title compound was obtained.

m.p. (hydrochloride): 228° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.89(2H, br-d), 2.12(2H, m), 2.91(2H, t, J=8.4 Hz), 3.12(2H, m),3.21(2H, m), 3.28(2H, m), 3.34(2H, t, J=8.4 Hz), 3.63(2H, br-d),3.76(1H, m), 6.60(1H, d, J=7.4 Hz), 6.61(1H, t, J=7.4 Hz), 7.02(1H, t,J=7.4 Hz), 7.05(1H, d, J=7.4 Hz), 7.52(2H, d, J=8.0 Hz), 7.84(2H, d,J=8.0 Hz).

FAB-Mass: 332(MH+).

Example 22: Synthesis of1-[1-(3-hydroxymethylphenethyl)piperidin-4-yl]indoline

3-(t-Butyl)dimethylsilyloxymethylphenethyl bromide (0.22 g) was treatedas in Example 2 to give the title compound (0.116 g) as a pale yellowoil (yield: 31.9%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.75-1.84(4H,m), 2.15(2H,m), 2.63(2H,m), 2.84(2H, m), 2.95(2H, t,J=8.4 Hz), 3.14(2H, br-t), 3.37(1H, m), 3.39(2H, t, J=8.4 Hz), 4.68(2H,s), 6.39(1H, d), 6.60(1H, t), 7.03(2H, m), 7.12-7.35(4H, m).

Next, hydrochloric acid (0.372 g) was added to the product to give asalt followed by recrystallization from ethanol-acetone mixtures. Thus,the hydrochloride of the title compound was obtained.

m.p.: 218° C.

Example 23: Synthesis of1-[1-(4-hydroxymethylphenethyl)piperidin-4-yl]indoline

4-(2-Bromoethyl)benzyl alcohol (0.2 g) was treated as in Example 2 togive the title compound (0.177 g) as a pale yellow oil (yield: 53.7%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.79(4H, m), 2.12(2H, dt, J=2.8, 11.6 Hz), 2.59(2H, m), 2.81(2H,m), 2.94(2H, t, J=8.4 Hz), 3.12(2H,br-d), 3.38(2H, t, J=8.4 Hz),3.40(1H, m), 4.65(2H, s), 6.42(1H, d, J=8.0 Hz), 6.61(1H, t, J=8.0 Hz),7.03(1H, t, J=8.0 Hz), 7.05(1H, d, J=8.0 Hz), 7.21(2H, d, J=8.0 Hz),7.49(2H, d, J=8.0 Hz), 8.11(1H, s).

Next, hydrochloric acid was added to the product to give thehydrochloride of the title compound.

FAB-Mass; 337 (MH+).

Example 24: Synthesis of1-{1-[4-(2-hydroxyethyl)phenethyl]piperidin-4-yl}indoline

4-[2-(t-Butyldimethylsilyloxy)ethyl]phenethyl bromide (0.2 g) wastreated as in Example 2 to give a pale yellow oil (0.113 g). Then thisproduct was dissolved in tetrahydrofuran (1.0 ml). To the resultantsolution was added a 2.0 M solution (0.49 ml) of tetrabutylammoniumfluoride in tetrahydrofuran and the resultant mixture was stirred atroom temperature for 1.5 hr. The liquid reaction mixture wasconcentrated under reduced pressure to give the title compound (0.086 g)as a yellow oil

(yield: quantitative).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.88(4H, m), 2.31(2H, m), 2.75(2H, m), 2.85(2H, t, J=6.4 Hz),2.95(2H, t, J=8.4 Hz), 3.21(2H, m), 3.24(2H, m), 3.40(2H, t, J=8.4 Hz),3.85(2H, t, J=6.4 Hz), 6.41(1H, d), 6.60(1H, t), 7.03(2H, m), 7.18(4H,s).

Then oxalic acid (0.372 g) was added to the above product to give theoxalate as a brown oil.

FAB-Mass: 351 (MH+).

Example 25: Synthesis of1-{4-[(1-hydroxyethyl)phenethyl]piperidin-4-yl}indoline

4-(1-Hydroxyethyl)phenethyl bromide (0.2 g) was treated as in Example 2to give the title compound (0.044 g) as a yellow oil (yield: 12.6%).

Then oxalic acid (11 mg) was added to the above product to give a saltfollowed by recrystallization from ethanol to give the oxalate.

m.p. (oxalate): 132° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.30(3H, d, J=6.4 Hz), 1.86(4H, m), 2.88(2H, t, J=8.0 Hz),2.92(4H, m), 3.15(2H, m), 3.32(2H, t, J=8.4 Hz), 3.54(2H, m), 3.67(1H,m), 4.69(1H, q, J=6.7 Hz), 6.51(1H, d, J=8.0 Hz), 6.55(1H, t, J=8.0 Hz),6.99(1H, t, J=8.0 Hz), 7.02(1H, d, J=8.0 Hz), 7.22(2H, d, J=8.0 Hz),7.30(1H, d, J=8.0 Hz).

FAB-Mass: 351(MH+).

Example 26: Synthesis of1-{1-[4-(2-hydroxyethoxy)phenethyl]piperidin-4-yl}indoline

N,N-Dimethylformamide (2.5 ml) was added to1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline (0.1 g), potassiumcarbonate (0.081 g) and 1-bromo-2-di(t-butyl)dimethylsilyloxyethane(0.20 g) and the resultant mixture was heated and stirred at 80° C. for28 hr. After allowing to cool, it was extracted with ethyl acetate (200ml), washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate system) to give acolorless oil. Then this product was dissolved in tetrahydrofuran (1.3ml) anda 2.0 Msolution (0.88 ml) of tetrabutylammonium fluoride intetrahydrofuran was added thereto followed by stirring the mixture atroom temperature for 1 hr. The resultant mixture was extracted withethyl acetate (200 ml), washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (0.124 g) as a colorless oil (yield:69.0%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.80(4H, m), 2.11(2H, dt, J=3.2, 11.6 Hz), 2.58(2H, m), 2.76(2H,m), 2.94(2H, t, J=8.4 Hz), 3.12(2H, br-d), 3.39(2H, t, J=8.4 Hz),3.40(1H, m), 3.94(2H, t, J=8.4 Hz), 4.06(2H, t, J=8.4 Hz), 6.40(1H, d,J=7.6 Hz), 6.60(1H, t, J=7.6 Hz), 6.85(2H, d, J=8.4 Hz), 7.04(2H, m),7.13(2H, d, J=8.4 Hz).

ESI-Mass: 367.2(MH+).

Next, hydrochloric acid was added to the above product to give thehydrochloride of the title compound as colorless crystals.

m.p. (hydrochloride): 229° C.

Example 27: Synthesis of1-[1-(4-trifluoromethylphenethyl)piperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (1.0 g) and 4-trifluoromethylphenylaceticacid (1.0 g) were treated as in Example 8 to give the hydrochloride(0.98 g) of the title compound as a white powder (yield: 48%).

m.p. (hydrochloride): 212° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.89(2H, m), 1.94-2.09(2H, m), 2.88(2H, t, J=8 Hz),3.02-3.20(4H, m), 3.28-3.36(4H, m), 3.60-3.79(3H, m), 6.52-6.58(2H, m),6.96-7.04(2H,m), 7.53(2H, d, J=8 Hz), 7.72(2H, d, J=8 Hz).

FAB-Mass: 375(MH+).

Example 28: Synthesis of1-[1-(4-methanesulfonylphenethyl)piperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (200 mg) and 4-methane-sulfonylphenethylbromide (290 mg) were treated as in Example 2 to give the title compound(180 mg) as a white powder (yield: 43%).

m.p. (hydrochloride): 208-210° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.69-1.86(4H, m), 2.10-2.18(2H, m), 2.61-2.67(2H, m),2.87-2.98(4H, m), 3.04(3H, s), 3.06-3.14(2H, m), 3.35-3.44(3H, m),6.41(1H, d, J=8 Hz), 6.60(1H, t, J=8 Hz), 7.01-7.06(2H, m), 7.41(2H, d,J=8 Hz), 7.85(2H, d, J=8 Hz).

FAB-Mass: 385(MH+).

Example 29: Synthesis of 1-[1-(4-nitrophenethyl)piperidin-4-yl]indoline

1-(Piperazin-4-yl)indoline (2.00 g) was dissolved in dimethylformamide(20 ml) and 4-(2-bromoethyl)nitrobenzene (10.0 g) and triethylamine (2.9ml) were added thereto followed by stirring the resultant mixture at100° C. overnight. After adding water to the reaction solution,extracted with ethyl acetate, the organic layer was washed with brineand dried over magnesium sulfate. After distilling off the solvent, theobtained residue was purified by silica gel column chromatography(hexane/ethyl acetate system) to give the title compound (1.05 g) as aslightly yellow solid.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.70-1.90(4H, m), 2.14-2.22(2H, m), 2.64-2.72(4H, m),2.90-3.00(2H, m), 3.08-3.16(2H, m), 3.36-3.46(3H, m), 6.41(1H, d, J=7.6Hz), 6.61(1H, d, J=7.6 Hz), 7.02-7.08(2H, m), 7.35-7.40(2H, m),8.13-8.18(2H, m).

FAB-Mass: 352(MH+).

m.p.: 95-97° C.

Example 30: Synthesis of 1-[1-(4-aminophenethyl)piperidin-4-yl]indoline

1-[1-(4-Nitrophenethyl)piperidin-4-yl]indoline (780 g) was dissolved inmethanol (7 ml) and conc. hydrochloric acid (0.5 ml) was added dropwiseinto the resultant solution. Subsequently, the resultant mixture wascatalytically reduced under atmospheric pressure in the presence of apalladium catalyst. After filtering off the catalyst, a 1 N aqueoussolution of sodium hydroxide was added to the filtrate followed byextraction with chloroform. The organic layer was washed with brine anddried over magnesium sulfate. After evaporating the solvent, the titlecompound (620 mg) was obtained as an oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.70-1.85(4H, m), 2.06-2.15(2H, m), 2.52-2.60(2H, m),2.67-2.75(2H, m), 2.94(2H, t, J=8.2 Hz), 3.08-3.16(2H, m), 3.35-3.45(3H,m), 3.57(2H, br-s), 6.41(1H, d, J=8.0 Hz), 6.57-6.67(3H, m),6.97-7.02(2H, m), 7.05(1H, d, J=8.0 Hz).

FAB-Mass: 322(MH+).

Example 31: Synthesis of1-[1-(4-methylsulfonylaminophenethyl)piperidin-4-yl]-indoline and1-{1-[4-bis(methyl-sulfonyl)aminophenethyl]piperidin-4-yl)indoline

1-[1-(4-Aminophenethyl)piperidin-4-yl]indoline (140 mg) was dissolved inmethylene chloride (2 ml). Under ice cooling, methanesulfonyl chloride(0.12 ml) and triethylamine (0.1 ml) were added to the resultantsolution f ollowed by stirring for 45 min. After adding a 10% aqueoussolution of potassium carbonate, the reaction solution was extractedwith ethyl acetate. The organic layer was washed with brine and dri edover magnesium sulfate. After evaporating the solvent, the resultingresidue (150 mg) was purified by NH-silica gel column chromatography(hexane/ethyl acetate system) to successively give 1-{1-[4-bis(methylsulfonyl)aminophenethyl]piperidin-4-yl}indoline (50 mg) and1-[1-(4-methylsulfonylaminophenethyl)piperidin-4-yl]indoline (35 mg)each as an oil.

(1) 1-{1-[4-bis(methylsulfonyl)aminophenethyl]piperidin-4-yl}indoline

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.71-1.87(4H, m), 2.09-2.18(2H, m), 2.60-2.66(2H, m),2.83-2.89(2H, m), 2.95(2H, t, J=8.4 Hz), 3.08-3.15(2H, m), 3.35-3.45(3H,m), 3.39(6H, s), 6.41(1H, d, J=7.5 Hz), 6.60(1H, t, J=7.5 Hz),7.01-7.07(2H, m), 7.25-7.33(4H, m).

FAB-Mass: 478(MH+).

(2) 1-[1-(4-methylsulfonylaminophenethyl)piperidin-4-yl]indoline

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.52-1.66(4H, m), 2.00-2.08(2H, m), 2.64-2.70(2H, m),2.80-2.86(2H, m), 2.96-3.02(2H, m), 3.25-3.40(3H, m), 3.32(3H, s),6.41(1H, d, J=7.4 Hz), 6.48(1H, t, J=7.4 Hz), 6.91-6.99(2H, m),7.07-7.19(4H, m).

FAB-Mass: 400(MH+).

Example 32: Synthesis of1-[1-(4-acetamidophenethyl)piperidin-4-yl]indoline

1-[1-(4-Aminophenethyl)piperidin-4-yl]indoline (310 mg) was dissolved inmethylene chloride (3 ml). Under ice cooling, acetyl chloride (0.103 ml)was added to the resultant solution followed by stirring the obtainedmixture for 45 min. After adding a 10% aqueous solution of potassiumcarbonate, the reaction solution was extracted with ethyl acetate. Thenthe organic layer was washed with brine and dried over magnesiumsulfate. After evaporating the solvent, the resulting residue waspurified by NH-silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (200 mg) as an oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.70-1.86(4H, m), 2.08-2.16(2H, m), 2.17(3H, s), 2.56-2.62(2H,m), 2.76-2.82(2H, m), 2.95(2H, t, J=8.4 Hz), 3.08-3.14(2H, m),3.35-3.44(3H, m), 6.41(1H, d, J=7.5 Hz), 6.60(1H, t, J=7.5 Hz), 7.04(1H,t, J=7.5 Hz), 7.10(1H, br-s), 7.16(2H, d, J=8.4 Hz), 7.40(2H, d, J=8.4Hz).

FAB-Mass: 364(MH+).

Example 33: Synthesis of1-[1-(4-ethylaminophenethyl)piperidin-4-yl]indoline

1-[1-(4-Acetaminophenethyl)piperidin-4-yl]indoline (135 mg) wasdissolved in tetrahydrofuran (5 ml). After adding lithium aluminumhydride (28 mg) at room temperature, the resultant mixture was heatedunder reflux for 2 hr. After adding water, the reaction solution wasextracted with ethyl acetate. Then the organic layer was washed withbrine and dried over magnesium sulfate. After evaporating the solvent,the obtained residue was purified by NH-silica gel column chromatography(hexane/ethyl acetate system) to give the title compound (40 mg) as anoil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.25(3H, t, J=7.1 Hz), 1.72-1.86(4H, m), 2.06-2.14(2H, m),2.54-2.60(2H,m), 2.68-2.76(2H,m), 2.91-2.98(2H, m), 3.09-3.16(3H, m),3.35-3.44(4H, m), 6.41(1H, d, J=8.0 Hz), 6.54-6.70(3H, m), 7.00-7.07(4H,m).Example 34: Synthesis of 1-[1-(4-hydroxyiminomethylphenethylpiperidin-4-yl]indoline

4-(2-Bromoethyl)benzaldoxime (0.49 g) was treated as in Example 2 togive the title compound (0.480 g) as pale yellow crystals (yield:70.1%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.87(4H, m), 2.19(2H, dt, J=3.0, 11.2 Hz), 2.68(2H, m), 2.89(2H,m), 2.93(2H, t, J=8.4 Hz), 3.20(2H, br-d), 3.40(2H, t, J=8.4 Hz),3.43(1H, m), 6.42(1H, d, J=8.0 Hz), 6.61(1H, t, J=8.0 Hz), 7.03(1H, t,J=8.0 Hz), 7.05(1H, d, J=8.0 Hz), 7.21(2H, d, J=8.0 Hz),7.49(2H, d,J=8.0 Hz), 8.11(1H, s).

Next, hydrochloric acid was added to the product to give the hygroscopicand amorphous hydrochloride of the title compound was obtained.

FAB-Mass: 350(MH+).

Example 35: Synthesis of1-[1-(4-aminomethylphenethyl)piperidin-4-yl]indoline

1-[1-(4-Hydroxyiminomethylphenethyl)piperidin-4-yl]indoline (2.71 g) wasdissolved in tetrahydrofuran (40 ml). Under ice cooling, lithiumaluminum hydride (0.59 g) was added thereto and the resultant mixturewas heated under reflux for 2 hr. Then the reaction mixture was icecooled again followed by the addition of water (0.6 ml), a 5 N aqueoussolution (0.6 ml) of sodium hydroxide and further water (1.8 ml)thereto. The resulting precipitate was filtered off and the filtrate waswashed with ethyl acetate and concentrated under reduced pressure togive the title compound (1.462 g) as a pale yellow oil (yield: 56.2%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.58(2H, m), 1.79(4H, m), 2.12(2H, dt, J=3.0, 11.6 Hz), 2.61(2H,m), 2.81(2H, m), 2.95(2H, t, J=8.4 Hz), 3.13(2H, br-d), 3.39(2H, t,J=8.4 Hz), 3.40(1H, m), 3.84(2H, s), 6.42(1H, d, J=7.6 Hz), 6.60(1H, t,J=7.6 Hz), 7.04(1H, t, J=7.6 Hz), 7.05(1H, d, J=7.6 Hz), 7.18(2H, d,J=8.4 Hz), 7.24(2H, d, J=8.4 Hz).

Next, hydrochloric acid was added to the product to give the hygroscopicand amorphous hydrochloride of the title compound was obtained.

FAB-Mass: 336(MH+).

Example 36: Synthesis of1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indoline

1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]indoline (0.6 g) wasdissolved in tetrahydrofuran (9.0 ml). Under ice cooling, acetylchloride (0.14 ml) was added dropwise thereinto and the resultantmixture was stirred for 2 hr. After adding a saturated aqueous solutionof sodium bicarbonate, the mixture was extracted with ethyl acetate,washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified byCromatorex NH silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (0.518 g) as a pale yellow oil(yield: 79.2%).

Next, hydrochloric acid was added to the product to give the paleyellow, hygroscopic and amorphous hydrochloride of the title compound.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.86(3H, s), 1.90(2H, m), 2.08(2H, m), 2.90(2H, t, J=8.2 Hz),3.08(4H, m), 3.23(2H, m), 3.33(2H, t, J=8.2 Hz), 3.63(2H, br-d),3.74(1H, m), 4.22(2H, d, J=6.0 Hz), 6.58(1H, d, J=7.6 Hz), 6.59(1H, t,J=7.6 Hz), 7.01(1H, t, J=7.6 Hz), 7.05(1H, d, J=7.6 Hz), 7.23(4H, s),8.36(1H, t, J=6.0 Hz).

FAB-Mass: 378(MH+).

Example 37: Synthesis of1-[1-(4-chloroacetamidomethylphenethyl)piperidin-4-yl]indoline

1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]indoline (0.1 g) andchloroacetyl chloride (0.026 ml) were treated as in Example 36 to givethe title compound (0.074 g) as a pale yellow oil (yield: 62.1%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.79(4H, m), 2.12(2H, m), 2.61(2H, m), 2.82(2H, m), 2.94(2H, t,J=8.4 Hz), 3.12(2H, br-d), 3.39(2H, t, J=8.4 Hz), 3.40(1H, m), 4.13(2H,s), 4.46(2H, d, J=5.6 Hz), 6.41(1H, d, J=7.6 Hz), 6.60(1H, t, J=7.6 Hz),6.83(1H, br-s), 7.04(2H, t, J=8.0 Hz), 7.20(4H, m).

Next, oxalic acid (8 mg) was added to the above free compound to give asalt followed by recrystallization from a solvent mixture of ethanolwith isopropyl ether. Thus, the oxalate (0.054 g) of the title compoundwas obtained as colorless crystals.

m.p. (oxalate): 138° C.

FAB-Mass: 412(MH+).

Example 38: Synthesis of1-[1-(4-methanesulfonylaminomethylphenethyl)piperidin-4-yl]indoline

1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]indoline (0.120 g) andmethanesulfonyl chloride (0.030 ml) were treated as in Example 36 togive the title compound (0.078 g) as a pale yel low oil (yield: 54.5%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.85(4H, m), 2.20(2H, m), 2.66(2H, m), 2.86(2H, m), 2.89(3H, s),2.95(2H, t, J=8.7 Hz), 3.28(2H, m), 3.39(2H, t, J=8.7 Hz), 3.42(1H, m),4.30(2H, d, J=5.8 Hz), 4.63(1H, m), 6.41(1H, d, J=8 Hz), 6.61(1H, t, J=8Hz), 7.03(1H, t, J=8 Hz), 7.05(1H, d, J=8 Hz), 7.21(2H, d, J=8 Hz),7.28(2H, d, J=8 Hz).

Next, oxalic acid (18 mg) was added to the above free compound followedby recrystallization from a solvent mixture of acetone with water togive the oxalate of the title compound.

m.p. (oxalate): 199° C.

FAB-Mass: 414(MH+).

Example 39: Synthesis of1-[1-(4-propionylaminomethylphenethyl)piperidin-4-yl]-3-methylindoline

1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]-3-methylindoline (0.1 g)and propionyl chloride (0.028 ml) were treated as in Example 36 to givethe title compound (0.122 g) as a pale yellow oil (yield: quantitative).

Next, oxalic acid (13 mg) was added thereto followed byrecrystallization from ethyl acetate to give the oxalate (0.064 g) ofthe title compound as colorless crystals.

m.p. (oxalate): 96-105° C

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.02(3H, t, J=8.4 Hz), 1.86(2H, m), 2.10(2H, m), 2.13(2H, q,J=8.4 Hz), 2.81(2H, m), 2.88(2H, t, J=8.4 Hz), 2.91(2H, m), 3.07(2H, m),3.10(2H, t, J=8.4 Hz), 3.49(2H, br-d), 3.64(1H, m), 4.22(2H, s),6.52(2H, m), 7.01(2H, m), 7.20(4H, m).

FAB-Mass: 392(MH+).

Example 40: Synthesis of1-[1-(4-carbamoylphenethyl)piperidin-4-yl]indoline

4-Carbamoylphenethyl bromide (0.135 g) was treated as in Example 2 togive the title compound (0.097 g) as pale yellow crystals (yield:56.6%).

Next, oxalic acid (13 mg) was added thereto to give the amorphousoxalate of the title compound.

m.p. (oxalate): 178-193° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.78(4H, m), 2.61(2H, m), 2.87(2H, t, J=8.4 Hz), 2.94(4H, m),3.31(2H, t, J=8.4 Hz), 3.34(2H, m), 3.55(1H, m), 6.48(1H, d, J=7.6 Hz),6.53(1H, t, J=7.6 Hz), 6.98(1H, t, J=7.6 Hz), 7.01(1H, d, J=7.6 Hz),7.31(1H, m), 7.34(2H, d, J=8.4 Hz), 7.82(2H, d, J=8.4 Hz), 7.93(1H, m).

ESI-Mass: 350.1(MH+).

Example 41: Synthesis of1-[1-(4-N-isopropylcarbamoylmethylphenethyl)piperidin-4-yl]indoline

N-Isopropyl-4-(2-bromoethyl)phenylacetamide (0.029 g) was treated as inExample 2 to give the title compound (0.040 g) as colorless crystals(yield: 92.1%).

Next, oxalic acid (5 mg) was added thereto to give the amorphous oxalateof the title compound.

m.p. (oxalate): 88-96° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.64(6H, d, J=6.8 Hz), 1.82(4H, m), 2.82-2.92(6H, m), 3.06(2H,m), 3.31(2H, m), 3.33(2H, s), 3.46(2H, m), 3.63(1H, m), 9.79(1H, q,J=6.8 Hz), 6.50(1H, d, J=8 Hz), 6.54(1H, t, J=8 Hz), 6.98(1H, t, J=8Hz), 7.01(1H, d, J=8 Hz), 7.19(4H, s), 7.93(1H, d, J=8 Hz).

ESI-Mass: 406.25(MH+).

Example 42: Synthesis of1-[1-(4-sulfamoylphenethyl)piperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (300 mg) and 4-sulfamoylphenethyl bromide(400 mg) were treated as in Example 2 to give the title compound (60 mg)as a pale yellow powder (yield: 10%).

m.p.: 207-210° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.70-1.87(4H, m), 2.11-2.20(2H, m), 2.60-2.66(2H, m),2.86-2.98(4H, m), 3.08-3.15(2H, m), 3.34-3.45(3H, m), 6.41(1H, d, J=8Hz), 6.61(1H, d, J=8 Hz), 7.01-7.08(2H, m), 7.36(2H, d, J=8 Hz),7.85(2H, d, J=8 Hz).

FAB-Mass: 386(MH+).

Example 43: Synthesis of1-{1-[(3-(2-hydroxyethoxy)phenethyl]piperidin-4-yl}indoline

3-[2-(t-Budyldimethylsilyloxy)ethoxy]phenethyl bromide (0.33 g) wastreated as in Example 24 to give the title compound (0.197 g) as ayellow oil (yield: 53.8%)

Next, oxalic acid (48 mg) was added thereto to give the oxalate of thetitle compound.

m.p. (oxalate): 118° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.86(4H, m), 2.88(2H, t, J=8.2 Hz), 2.92(4H, m), 3.17(2H, m),3.31(2H, t, J=8.2 Hz), 3.53(2H, br-d), 3.67(1H, m), 3.71(2H, t, J=9.0Hz), 3.08(2H, t, J=9.0 Hz), 6.52(1H, d, J=7.6 Hz), 6.55(1H, t, J=7.6Hz), 6.83(2H, m), 6.87(1H, br-s), 6.99(1H, t, J=7.6 Hz), 7.02(1H, d,J=7.6 Hz), 7.24(1H, t, J=8.4 Hz).

FAB-Mass: 367(MH+).

Example 44: Synthesis of1-{1-[4-(2-dimethylaminoethoxy)phenethyl]piperidin-4-yl}indoline

N,N-Dimethylformamide (2.5 ml) was added to1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline (0.1 g), potassiumcarbonate (0.081 g) and 2-dimethylaminoethyl chloride hydrochloride(0.078 g) followed by stirring at 80° C. overnight (12 hr). Afterallowing to cool, the resultant mixture was mixed with ethyl acetate(200 ml) and the layers were separated. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(0.052 g) as a brown oil (yield: 27.0%).

Next, hydrochloric acid was added thereto to give the hydrochloride ofthe title compound.

m.p. (hydrochloride): 258-259° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.87(2H, m), 2.12(2H, m), 2.82(6H, m), 2.91(2H, t, J=8.4 Hz),3.06(4H, m), 3.21(2H, m), 3.34(2H, t, J=8.4 Hz), 3.48(2H, m), 3.63(2H,br-d), 3.75(1H, m), 4.37(2H, t, J=4.8 Hz), 6.59(1H, d, J=8.0 Hz),6.60(1H, t, J=8.0 Hz), 6.98(2H, d, J=8.6 Hz), 7.01(1H, t, J=8.0 Hz),7.05(1H, d, J=8.0 Hz), 7.24(2H, d, J=8.6 Hz).

ESI-Mass: 394.2(MH+).

Example 45: Synthesis of1-{1-[3,4-di(hydroxymethyl)phenethyl]piperidin-4-yl}indoline

3,4-Di[(t-butyl)dimethylsilyloxymethyl]phenethyl bromide (0.421 g) wastreated as in Example 24 to give the title compound (0.318 g) as a paleyellow oil (yield: 98.6%).

Next, hydrochloric acid was added thereto to give a salt followed byrecrystallization from ethanol to give the hydrochloride (0.617 g) ofthe title compound as colorless crystals (yield: 47.1%).

m.p. (hydrochloride): 178° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.89(2H, m), 1.04(2H, m), 2.90(2H, t, J=8.0 Hz), 3.08(4H, m),3.25(2H, m), 3.33(2H, t, J=8.0 Hz), 3.66(2H, br-d), 3.73(1H, m),4.50(2H, s), 4.53(2H, s), 6.55(1H, d, J=7.6 Hz), 6.58(1H, t, J=7.6 Hz),7.01(1H, t, J=7.6 Hz), 7.04(1H, d, J=7.6 Hz), 7.14(1H, dd, J=1.6, 8.0Hz), 7.32(1H, d, J=1.6 Hz), 7.34(1H, d, J=8.0 Hz).

FAB-Mass: 367(MH+).

Example 46: Synthesis of1-{1-[3,4-(methylenedioxy)phenethyl]piperidin-4-yl}indoline

3,4-(Methylenedioxy)phenylacetic acid (0.198 g) was treated as inExample 11 to give the title compound (0.304 g) as a colorless oil(yield: 89.8%).

Next, hydrochloric acid was added thereto to give a salt followed byrecrystallization from ethanol to give the hydrochloride of the titlecompound as colorless crystals.

m.p. (hydrochloride): 236° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.88(2H, br-d), 2.12(2H, m), 2.93(2H, t, J=8.0 Hz), 3.03(4H, m),3.20(2H, m), 3.37(2H, t, J=8.0 Hz), 3.61(2H, br-d), 3.78(1H, m),5.99(2H, s), 6.74(1H, d, J=8.0 Hz), 6.88(2H, m), 7.06(2H, m).

FAB-Mass: 361(MH+).

Example 47: Synthesis of1-{1-[2-(4-chlorophenylsulfonylamino)ethyl]piperidin-4-yl}indoline

1-[1-(2-Aminoethyl)piperidin-4-yl]indoline (113 mg) was dissolved inchloroform (3 ml). Under ice cooling, 4-chlorobenzenesulfonyl chloride(97 mg) was added thereto and the resultant mixture was stirred for 6hr. After adding water, the reaction solution was extracted withchloroform. The organic layer was washed with brine and dried overmagnesium sulfate. After evaporating the solvent, the resulting residue(205 mg) was purified by NH-silica gel column chromatography(methanol/methylene chloride system) to give the title compound (134 mg)as an oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.54-1.66(2H, m), 1.71-1.78(2H, m), 1.99-2.07(2H, m), 2.42(2H, t,J=5.8 Hz), 2.70-2.76(2H, m), 2.94-3.02(4H, m), 3.28-3.40(3H, m),5.30(1H, br-s), 6.36(1H, d, J=8.0 Hz), 6.59-6.63(1H, m), 7.00-7.08(2H,m), 7.47-7.52(2H, m), 7.80-7.84(2H, m).

FAB-Mass: 420(MH+).

Example 48: Synthesis of1-{1-[2-(4-methoxyphenylsulfonylamino)ethyl]piperidin-4-yl}indoline

1-[1-(2-Aminoethyl)piperidin-4-yl]indoline (113 mg) was dissolved inchloroform (3 ml). Under ice cooling, 4-methoxybenzenesulfonyl chloride(95 mg) was added thereto and the resultant mixture was stirred at roomtemperature overnight. After adding water, the reaction solution wasextracted with chloroform. The organic layer was washed with brine anddried over magnesium sulfate. After evaporating the solvent, theresulting residue (80 mg) was purified by NH-silica gel columnchromatography (methanol/methylene chloride system) to give the titlecompound (45 mg) as an oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.54-1.76(4H, m), 1.96-2.04(2H, m), 2.40(2H, t, J=5.8 Hz),2.67-2.74(2H, m), 2.93-3.00(4H, m), 3.27-3.36(1H, m), 3.37(2H, t, J=8.4Hz), 3.86(3H, s), 5.19(1H, br-s), 6.36(1H, d, J=8.0 Hz), 6.58-6.62(1H,m), 6.95-7.08(4H, m), 7.78-7.83(2H, m).

FAB-Mass: 416(MH+).

Example 49: Synthesis of1-{1-[2-(4-pyridyl)ethyl]piperidin-4-yl}indoline

1-(4-Piperidyl)indoline (0.1 g) was dissolved in ethanol (5 ml). Afteradding 4-vinylpyridine (0.16 ml), the resultant mixture was heated underreflux in a nitrogen atmosphere for 12 hr. Then the reaction solutionwas concentrated under reduced pressure and purified by silica gelcolumn chromatography (toluene/acetone system) to give the titlecompound (0.064 g) as a colorless oil (yield: 42.5%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.74-1.85(4H, m), 2.15(2H, dt, J=2.8, 12.0 Hz), 2.64(2H, m),2.82(2H, m), 2.95(2H, t, J=8.4 Hz), 3.10(2H, br-d), 3.39(2H, t, J=8.4Hz), 3.40(1H, m), 6.41(1H, d, J=8.0 Hz), 6.61(1H, t, J=8.0 Hz), 7.04(1H,t, J=8.0 Hz), 7.05(1H, d, J=8.0 Hz), 7.14(2H, dd, J=2.0, 4.8 Hz),8.50(2H, dd, J=2.0, 4.8 Hz).

Next, hydrochloric acid was added to the above product to give thehydrochloride of the title compound as a hygroscopic pale yellowamorphous solid.

FAB-Mass: 308(MH+).

Example 50: Synthesis of1-{1-[2-(2-pyridyl)ethyl]piperidin-4-yl}indoline

2-Vinylpyridine (0.16 ml) was treated as in Example 49 to give the titlecompound (0.041 g) as a colorless oil (yield: 27.2%).

Next, hydrochloric acid was added thereto to give a salt followed byrecrystallization from ethanol-isopropyl-ether mixtures to give thehydrochloride (0.036 g) of the title compound.

m.p. (hydrochloride): 258-260° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.89(2H, br-d), 2.16(2H, m), 2.93(2H, t, J=8.0 Hz), 3.20(2H, m),3.38(2H, t, J=8.0 Hz), 3.61(6H, m), 3.83(1H, br-t), 6.66(2H, m),7.05(1H, t, J=8 Hz), 7.08(1H, d, J=8 Hz), 7.89(1H, m), 8.00(1H, d, J=7.6Hz), 8.47(1H, m), 8.82(1H, d, J=5.2 Hz).

FAB-Mass: 308(MH+).

Example 51: Synthesis of1-{1-[2-(3-pyridyl)ethyl]piperidin-4-yl}indoline

3-(2-Bromoethyl)pyridine (0.481 g) was treated as in Example 2 to givethe title compound (0.601 g) as a pale yellow oil (yield: 75.5%).

Next, oxalic acid was added thereto to give a salt followed byrecrystallization from ethanol to give the oxalate of the titlecompound.

m.p. (oxalate): 174° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.92(4H, m), 2.87(2H, t, J=8.4 Hz), 3.04(4H, m), 3.10(2H, m),3.31(2H, t, J=8.4 Hz), 3.61(2H, br-d), 3.72(1H, m), 6.53(1H, d, J=7.6Hz), 6.56(1H, t, J=7.6 Hz), 7.00(1H, t, J=7.6 Hz), 7.03(1H, d, J=7.6Hz), 7.39(1H, dd, J=4.8, 7.6 Hz), 7.74(1H, ddd, J=1.6, 1.6, 7.6 Hz),8.48(1H, dd, J=1.6, 4.8 Hz), 8.53(1H, J=1.6 Hz).

ESI-Mass: 308(MH+).

Example 52: Synthesis of1-{1-[2-(2-methoxy-5-pyridyl)ethyl]piperidin-4-yl}indoline

1-Bromo-2-(2-methoxypyridin-5-yl)ethane (1.221 g) was treated as inExample 2 to give the title compound (1.394 g) as a pale yellow oil(yield: 82.6%).

Next, oxalic acid (0.372 g) was added thereto to give a salt followed byrecrystallization from ethanol to give the oxalate of the titlecompound.

m.p. (oxalate): 173° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-1.95(4H, br-d), 2.88(2H, t, J=8.4 Hz), 2.94 (4H, m),3.15(2H, m), 3.31(2H, t, J=8.4 Hz), 3.53(2H, br-d), 3.68(1H, m),3.83(3H, s), 6.52(1H, d, J=8.0 Hz), 6.55(1H, t, J=8.0 Hz), 6.81(1H, d,J=8.4 Hz), 6.99(1H, t, J=8.0 Hz), 7.02(1H, d, J=8.0 Hz), 7.64(1H, dd,J=2.4, 8.4 Hz), 8.08(1H, d, J=2.4 Hz).

FAB-Mass; 338(MH+).

Example 53: Synthesis of1-{1-[2-(3-methoxypyridin-5-yl)-ethyl]piperidin-4-yl}indoline

5-(2-Bromoethyl)-3-methoxypyridine (0.181 g) was treated as in Example 2to give the title compound (1.104 g) as a yellow oil (yield: 37.1%).

Next, oxalic acid (28 mg) was added thereto to give a salt followed byrecrystallization from ethanol to give the oxalate (0.077 g) of thetitle compound.

m.p. (oxalate): 220° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.89(4H, m), 2.88(2H, t, J=8.4 Hz), 3.99(2H, m), 3.22(2H, m),3.31(2H, t, J=8.4 Hz), 3.54(2H, br-d), 3.68(1H, m), 3.83(3H, s),6.52(1H, d, J=7.6 Hz), 6.55(1H, t, J=7.6 Hz), 6.99(1H, t, J=7.6 Hz),7.02(1H, d, J=7.6 Hz), 7.35(1H, t, J=2.0 Hz), 8.11(1H, t, J=2.0 Hz),8.19(1H, t, J=2.0 Hz).

FAB-Mass: 338(MH+).

Example 54: Synthesis of1-{1-[2-(2-cyanopyridin-5-yl)ethyl]piperidin-4-yl}indoline

1-Bromo-2-(2-cyanopyridin-5-yl)ethane (0.406 g) was treated as inExample 2 to give the title compound (0.068 g) as a pale yellow oil(yield: 9.7%).

Next, oxalic acid (18 mg) was added thereto to give a salt followed byrecrystallization from ethanol to give the oxalate of the titlecompound.

m.p. (oxalate): 136° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.82(4H, m), 2.81(2H, m), 2.87(2H, t, J=8.2 Hz), 3.07(2H, m),3.14(2H, m), 3.31(2H, t, J=8.2 Hz), 3.44(2H, br-d), 3.63(1H, m),6.51(1H, d, J=7.6 Hz), 6.54(1H, t, J=7.6 Hz), 6.99(1H, t, J=7.6 Hz),7.01(1H, d, J=7.6 Hz), 8.01(2H, m), 8.71(1H, d, J=1.6 Hz).

FAB-Mass: 333(MH+).

Example 55: Synthesis of1-{1-[2-(2-hydroxymethylpyridin5-yl)ethyl]piperidin-4-yl}indoline

1-{1-[2-(2-Cyanopyridin-5-yl)ethyl]piperidin-4-yl}indoline (0.103 g) wasdissolved in toluene (1.5 ml). In a nitrogen atmosphere at −78° C., a1.5 M solution (0.44 ml) of diisobutylaluminum hydride in toluene wasadded thereto and the resultant mixture was stirred under the sameconditions for 1 hr. Then the reaction solution was poured into a 5%aqueous solution of sulfuric acid and basified with an aqueous solutionof sodium hydroxide. Next, diethyl ether was added and the layers wereseparated. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give thetitle compound (0.066 g) as a yellow oil (yield: 64.5%).

Free

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.79(4H, m), 2.13(2H, dt, J=2.8, 8.0 Hz), 2.60(2H, m), 2.80(2H,m), 2.97(2H, d, J=8.4 Hz), 3.10(2H, br-d), 3.39(2H, t, J=8.4 Hz),3.40(1H, m), 3.95(2H, s), 6.41(1H, d, J=7.6 Hz), 6.60 (1H, t, J=7.6 Hz),7.04 (1H, t, J=7. 6 Hz), 7.05 (1H, d, J=7.6 Hz), 7.21(1H, d, J=8.0 Hz),7.50(1H, dd, J=2.0, 8.0 Hz), 8.42(1H, d, J=2.0 Hz).

ESI-Mass: 338.3(MH+).

Next, oxalic acid (18 mg) was added to the above product to give theoxalate of the title compound as a hygroscopic amorphous solid.Example 56 Synthesis of1-{1-[2-(3-hydroxymethylpyridin-5-yl)ethyl]piperidin-4-yl}indoline

5-(2-Bromoethyl)-3-(t-butyl)dimethylsilyloxymethyl-pyridine (0.248g) wastreated as in Example 24 to give the title compound (0.150 g) as a paleyellow oil (yield: 61.4%).

Next, oxalic acid (40 mg) was added thereto to give a salt followed byrecrystallization from ethanol to give the oxalate (0.143 g) of thetitle compound.

m.p. (oxalate): 177° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.89(4H, m), 2.88(2H, t, J=8.4 Hz), 3.01(2H, m), 3.22(2H, m),3.32(2H, t, J=8.4 Hz), 3.57(2H, br-d), 3.69(1H, m), 4.53(2H, s),6.53(1H, d, J=7.6 Hz), 6.56(1H, t, J=7.6 Hz), 6.99(1H, t, J=7.6 Hz),7.02(1H, d, J=7.6 Hz), 7.66(1H, s), 8.39(1H, d, J=1.8 Hz), 8.41(1H, d,J=1.8 Hz).

FAB-Mass: 338(MH+).

Example 57: Synthesis of1-[1-(2,6-difluoro-3-pyridylethyl)piperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (300 mg) and2,6-difluoro-3-bromoethylpyridine (330 mg) were treated as in Example 2to give the hydrochloride (270 mg) of the title compound as a whitepowder (yield: 47%).

m.p. (hydrochloride): 202-204° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.82-1.91(2H, m), 2.00-2.13(2H, m), 2.88(2H, t, J=8 Hz),3.03-3.16(4H, m), 3.24-3.34(4H, m), 3.58-3.66(2H, m), 3.68-3.78(1H, m),6.54-6.61(2H, m), 6.96-7.05(2H, m), 7.17-7.22(1H, m), 8.10-8.18(1H, m).

FAB-Mass: 344(MH+).

Example 58: Synthesis of1-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}indoline

1-(4-Piperidyl) indoline (0.1 g) was treated as in Example 2 to give thetitle compound (0.057 g) as colorless crystals (yield: 37.2%).

Next, hydrochloric acid was added thereto to give a salt followed byrecrystallization from ethanol-isopropyl ether mixtures to give thehydrochloride of the title compound as colorless crystals.

m.p. (hydrochloride): 243° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.88(2H, br-d), 2.15(2H, m), 2.93(2H, t, J=8.4 Hz), 3.09 (2H, m),3.34 (6H, m), 3.64 (2H, br-d), 3.78 (1H, tt, J=3.6, 12 Hz), 6.66(2H, m),7.00(2H, m), 7.06(2H, m)), 7.42(1H, dd, J=1.2, 4.8 Hz).

FAB-Mass: 313(MH+).

Example 59: Synthesis of1-{1-[2-(3-thienyl)ethyl]piperidin-4-yl}indoline

3-(2-Bromoethyl)thiophene (0.19 g) was treated as in Example 2 to givethe title compound (0.105 g) as a colorless oil (yield: 68.6%).

Next, hydrochloric acid was added thereto to give a salt followed byrecrystallization from ethanol-isopropyl ether mixtures to give thehydrochloride of the title compound as colorless crystals.

m.p. (hydrochloride): 248° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.88 (2H, br-d), 2.04 (2H, m), 2.90 (2H, t, J=8.4 Hz), 3.08 (4H,m), 3.30 (2H, m), 3.32 (2H, t, J=8.4 Hz), 3.63 (2H, br-d), 3.74(1H, m),6.56(1H, d, J=7.6 Hz), 6.58(1H, t, J=7.6 Hz), 7.00 (H, t, J=7.6 Hz),7.04 (1H, d, J=7.6 Hz), 7.08 (1H, dd, J=1.2, 4.8 Hz), 7.34(1H, m),7.55(1H, dd, J=2.8, 4.8 Hz).

FAB-Mass: 313(MH+).

Example 60: Synthesis of 1-[1-(2-thiazolylethyl)piperidin-4-yl]indoline

2-(2-Bromoethyl)thiazole (0.46 g) was treated as in Example 2 to givethe title compound (0.102 g) as colorless crystals (yield: 14.4%).

Next, oxalic acid (15 mg) was added thereto to give a salt followed byrecrystallization from ethanol-acetone mixtures to give the oxalate ofthe title compound as colorless crystals.

m.p. (oxalate): 149° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.85(2H, m), 2.86(2H, m), 2.87(2H, t, J=8.4 Hz), 3.30(2H, m),3.31(2H, t, J=8.4 Hz), 3.40(4H, m), 3.47(2H, br-d), 3.63(1H, m),6.50(1H, d, J=7.6 Hz), 6.55(1H, t, J=7.6 Hz), 6.99(1H, t, J=7.6 Hz),7.02(1H, d, J=7.6 Hz), 7.65(1H, d, J=3.6 Hz), 7.75(1H, d, J=3.6 Hz).

FAB-Mass: 314(MH+).

Example 61: Synthesis of1-[1-(4-methyl-5-thiazolethyl)piperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (300 mg) and 4-methyl-5-thiazolethyl bromide(310 mg) obtained in the same manner as the one of Production Example 1were treated as in Example 2 to give the hydrochloride (140 mg) of thetitle compound as a gray powder (yield: 26%).

m.p. (hydrochloride): 222-225° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.82-1.89(2H, m), 1.95-2.10(2H, m), 2.37(3H, s), 2.87(2H, t, J=8Hz), 3.01-3.12(2H, m), 3.15-3.33(6H, m), 3.60-3.76(3H, m), 6.51-6.60(2H,m), 6.95-7.03(2H, m), 8.93(1H, s).

FAB-Mass: 328(MH+).

Example 62: Synthesis of1-{1-[(indol-3-yl)ethyl]-piperidin-4-yl}indoline

1-(Piperidin-4-yl)indoline (300 mg) and 3-(2-bromoethyl)indole (340 mg)obtained in the same manner as the one of Production Example 1 weretreated as in Example 2 to give the hydrochloride (410 mg) of the titlecompound as a brown powder (yield: 72%).

m.p. (hydrochloride): 240° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.82-1.91(2H, m), 1.93-2.08(2H, m), 2.89(2H, t, J=8 Hz),3.07-3.20(4H, m), 3.27-3.36(4H, m), 3.65-3.76(3H, m), 6.51-6.58(2H, m),6.96-7.04(3H,m), 7.06-7.11(1H, m), 7.24(1H, s), 7.35(1H, d, J=8 Hz),7.61(1H, d, J=8 Hz).

FAB-Mass: 346(MH+).

Example 63: Synthesis of1-{1-[2-(6-benzothiazolyl)-ethyl]piperidin-4-yl}indoline

6-(2-Bromoethyl)benzothiazole (0.073 g) was treated as in Example 2 togive the title compound (0.084 g) as apale yellow oil (yield: 70.0%).

Next, oxalic acid (21 mg) was added thereto to give a salt followed byrecrystallization from ethanol to give the oxalate of the titlecompound.

m.p. (oxalate): 197° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.87(4H, m), 2.88(2H, t, J=8.4 Hz), 2.95(2H, m), 3.13(2H, m),3.25(2H, m), 3.32(2H, t, J=8.4 Hz), 3.56(2H, m), 3.68(1H, m), 6.52(1H,d, J=8.0 Hz), 6.55(1H, t, J=8.0 Hz), 6.99(1H, t, J=8.0 Hz), 7.02(1H, d,J=8.0 Hz), 7.48(1H, dd, J=1.6, 8.4 Hz), 8.06(1H, d, J=8.4 Hz), 8.09(1H,d, J=1.6 Hz), 9.37(1H, s).

FAB-Mass: 364(MH+).

Example 64: Synthesis of1-[1-(5-methoxy-2-thienyl)ethylpiperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (300 mg) and (5-methoxy-2-thienyl)ethylbromide (400 mg) were treated as in Example 2 to give the hydrochloride(260 mg) of the title compound as a white powder (yield: 46%).

m.p. (hydrochloride): 204° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80-1.89(2H, m), 2.00-2.11(2H, m), 2.90(2H, t, J=8 Hz),3.00-3.28(6H, m), 3.32(2H, t, J=8 Hz), 3.55-3.62(2H, m),3.67-3.78(1H,m), 3.80(3H, s), 6.13(1H,d, J=4 Hz), 6.56-6.60(3H, m),6.97-7.04(2H, m), 10.79(1H, br-s).

FAB-Mass: 343(MH+).

Example 65: Synthesis of1-[1-(2-methoxy-5-thiazolyl)ethylpiperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (300 mg) and (2-methoxy-5-thiazolyl)ethylbromide (380 mg) were treated as in Example 2 to give the hydrochloride(340 mg) of the title compound as a white powder (yield: 60%).

m.p. (hydrochloride): 207° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80-1.86(2H, m), 1.92-2.03(2H, m), 2.89(2H, t, J=8 Hz),3.00-3.12(2H, m), 3.15-3.32(6H, m), 3.67-3.75(3H, m), 3.95(3H, s),6.50-6.59(2H, m), 6.94-7.07(3H, m), 10.36(1H, br-s).

FAB-Mass: 344(MH+).

Example 66: Synthesis of1-[1-(2-cyano-5-thiazolyl)ethylpiperidin-4-yl]indoline

1-(Piperidin-4-yl)indoline (190 mg) and (2-cyano-5-thiazolyl)ethylbromide (200 mg) were treated as in Example 2 to give the hydrochloride(21 mg) of the title compound as a gray powder (yield: 6.1%).

m.p. (hydrochloride): 209-211° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-2.00(4H, m), 2.89(2H, t, J=8 Hz),3.01-3.15(2H, m), 3.30(2H,t, J=8 Hz), 3.36-3.78(7H, m), 6.49-6.55(2H, m), 6.92-7.03(2H, m),8.02(1H, s).

FAB-Mass: 339(MH+).

Example 67: Synthesis of 1-(1-pyrazinylethylpiperidin-4-yl)indoline

A solution of 1-(piperidin-4-yl)indoline (500 mg) and vinylpyrazine (260mg) in o-dichlorobenzene (5 ml) was heated at 180° C. for 3 hr. Next,the reaction solution was purified by silica gel column chromatography(methylene chloride/ethanol system) and treated in a conventional mannerso as to give the oxalate (90 mg) of the title compound as a whitepowder (yield: 9.0%).

m.p. (oxalate): 168-170° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.75-1.83(4H, m), 2.80-2.91(4H, m), 3.11-3.20(2H, m),3.21-3.33(4H, m), 3.41-3.52(2H, m), 3.55-3.69(1H, m), 6.48(1H, d, J=8Hz), 6.53(1H, t, J=8 Hz), 6.95-7.00(2H, m), 8.53(1H, s), 8.57-8.59(1H,m), 8.63(1H, s).

FAB-Mass: 309(MH+).

Example 68: Synthesis of1-{1-[2-(4-bromopyrazol-1-yl)ethyl]piperidin-4-yl}indoline

1-(4-Piperidyl)indoline (162 mg) and 1-(2-bromoethyl)-4-bromopyrazole(200 mg) were treated as in Example 2 to give the hydrochloride (372 mg)of the title compound as beige crystals (yield: 67%).

m.p. (hydrochloride): 210-212° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83(2H, d, J=11.6 Hz), 2.00-2.12(2H, m), 2.88(2H, t, J=8.4 Hz),3.07(2H, q, J=11.2 Hz), 3.31(2H, t, J=8.4 Hz), 3.46-3.54(4H, m),3.66-3.76(1H, m), 4.63(2H, t, J=6.8 Hz), 6.56-6.64(2H, m), 6.97-7.06(2H,m), 7.64(1H, s), 8.11(1H, s), 11.10(1H, br-s).

ESI-Mass: 351(MH+).

Example 69: Synthesis of1-{1-[3-(4-fluorophenoxy)propyl]piperidin-4-yl}indoline

1-(Piperidin-4-yl)indoline (300 mg) and1-bromo-3-(4-fluorophenoxy)propane (420 mg) were treated as in Example 2to give the hydrochloride (330 mg) of the title compound as whiteneedles (yield: 56%).

m.p. (hydrochloride): 207-210° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80-1.87(2H, m), 1.91-2.20(4H, m), 2.88(2H, t, J=8 Hz),3.00-3.11(2H, m), 3.13-3.21(2H, m), 3.30(2H, t, J=8 Hz), 3.52-3.61(2H,m), 3.66-3.77(1H, m), 4.04(2H, t, J=6 Hz), 6.49-6.70(2H, m),6.92-7.03(4H, m), 7.08-7.15(2H, m).

FAB-Mass: 355(MH+).

Example 70: Synthesis of1-{1-[3-(4-hydroxymethylphenoxy)propyl]piperidin-4-yl}indoline

1-(4-Piperidyl)indoline (263 mg) and 4-(3-bromopropoxy)benzyl alcohol(389 mg) were treated as in Example 2 to give the title compound (422mg) as a pale orange amorphous solid (yield: 92%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.20-2.35(4H, m), 2.47-2.73(4H, m), 2.55(2H, t, J=7.4 Hz),2.94(2H, t, J=8.4 Hz), 3.07(2H, d, J=11.2 Hz), 3.35-3.43(1H, m),3.38(2H, t, J=8.4 Hz), 4.02(2H, t, J=6.4 Hz), 4.62(2H, s), 6.41(1H, d,J=8 Hz), 6.60(1H, dt, J=7.4 Hz, 0.8 Hz), 6.89(2H, d, J=8.8 Hz), 7.04(1H,ddd, J=8 Hz, 7.4 Hz, 0.8 Hz), 7.05(1H, d, J=7.4 Hz), 7.29(2H, d, J=8.8Hz).

ESI-Mass: 367(MH+).

Example 71: Synthesis of1-{1-[3-(4-hydroxyethylphenoxy)propyl]piperidin-4-yl}indoline

1-(4-Piperidyl)indoline (303 mg) and 4-(3-bromopropoxy)phenethyl alcohol(389 mg) were treated as in Example 2 to give the hydrochloride (500 mg)of the title compound as a beige amorphous solid (yield: 80%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.84(2H, d, J=13.2 Hz), 2.40-2.22(4H, m), 2.63(2H, t, J=7.2 Hz),2.90(2H, t, J=8.4 Hz), 3.05(2H, q, J=10.4 Hz), 3.12-3.19(2H, m),3.33(2H, t, J=8.4 Hz), 3.52(2H, t, J=7.2 Hz), 3.52-3.60(2H, m),3.70-3.80(1H, m), 4.01(2H, t, J=6 Hz), 6.58-6.68(2H, br-t), 6.83(2H, d,J=8.8 Hz), 7.01(1H, d, J=8 Hz), 7.05(1H, d, J=8 Hz), 7.11(2H, d, J=8.8Hz), 10.80(1H, br-s).

ESI-Mass: 381(MH+).

Example 72: Synthesis of1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}indoline

1-(Piperidin-4-yl)indoline (1.0 g) and4-chloro-1-(4-fluorophenyl)-1-butanone (1.1 g) were treated as inExample 2 to give the title compound (0.5 g) (yield: 27%).

A portion of this product was then treated in a conventional manner soas to give the hydrochloride of the title compound as a white powder.

m.p. (hydrochloride): 213° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80-1.88(2H, m), 1.94-2.10(4H, m), 2.88(2H, t, J=8 Hz),3.00-3.10(4H, m), 3.19(2H, t, J=8 Hz), 3.30(2H, t, J=8 Hz),3.50-3.60(2H, m), 3.67-3.78(1H, m), 6.52-6.58(2H, m), 6.96-7.03(2H, m),7.34-7.39(2H, m), 8.03-8.07(2H, m).

FAB-Mass: 367(MH+).

Example 73: Synthesis of1-{1-[4-(4-fluorophenyl)-4-hydroxybutyl]piperidin-4-yl}indoline

Sodium borohydride (38 mg) was added to a solution of1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}indoline (320 mg) inethanol (20 ml) and the resultant mixture was stirred for 5 hr. Afterconcentrating under reduced pressure, water and ethyl acetate were addedthereto and the layers were separated. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. Then the residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) and treated in aconventional manner so as to give the hydrochloride (250 mg) of thetitle compound as a gray powder (yield: 71%).

m.p. (hydrochloride): 174-175° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.55-2.00(6H, m), 2.87(2H, t, J=8 Hz), 2.95-3.05(4H, m), 3.28(2H,t, J=8 Hz), 3.46-3.54(2H, m), 3.62-3.71(1H, m), 4.57(1H, t, J=6 Hz),6.49-6.56(2H, m), 6.95-7.02(2H, m), 7.11-7.16(2H, m), 7.34-7.38(2H, m),9.71(1H, br-s).

FAB-Mass: 369(MH+).

Example 74: Synthesis of1-[1-(phthalimido-1-yl)ethylpiperidin-4-yl}indoline

1-(Piperidin-4-yl)indoline (500 mg) and N-(2-bromoethyl)phthalimide (750mg) were treated as in Example 2 to give the title compound (520 mg) asa colorless oil (yield: 55%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.59-1.81(4H, m), 2.09-2.20(2H, m), 2.68(2H, t, J=7 Hz), 2.90(2H,t, J=8 Hz), 3.08-3.15(2H, m), 3.30-3.41(1H, m), 3.32(2H, t, J=8 Hz),3.83(2H, t, J=7 Hz), 6.38(1H, d, J=8 Hz), 6.59(1H, t, J=8 Hz),7.00-7.08(2H, m), 7.68-7.73(2H, m), 7.80-7.87(2H, m).Example 75: Synthesis of1-[1-(4-fluorobenzamido)ethylpiperidin-4-yl]indoline

A solution of 1-[1-(phthalimido-1-yl)ethylpiperidin-4-yl]indoline (520mg) and hydrazine (100 mg) in ethanol (20 ml) was heated under refluxfor 5 hr. After cooling to room temperature, the resulting crystallineprecipitates were filtered off and the filtrate was concentrated. Theresulting residue was mixed with methylene chloride (30 ml), a 2 Naqueous solution (5 ml) of sodium hydroxide and 4-fluorobenzoyl chloride(250 mg) followed by vigorously stirring the resultant mixture at roomtemperature. After 1 hr, the reaction solution was diluted withmethylene chloride and the layers were separated. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate and purifiedby silica gel column chromatography (methylene chloride/ethanol system)followed by conversion into a hydrochloride. Thus the hydrochloride (160mg) of the title compound was obtained as a white powder (yield: 28%).

m.p. (hydrochloride): 221° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-2.02(4H, m), 2.88(2H, t, J=8 Hz),3.02-3.15(2H, m),3.20-3.31(4H, m), 3.60-3.75(5H, m), 6.49-6.56(2H, m), 6.95-7.02(2H, m),7.29-7.34(2H, m), 7.94-7.99(2H, m), 8.86(1H, t, J=6 Hz).

FAB-Mass: 368(MH+).

Example 76: Synthesis of1-{1-[1-(3,4-dimethoxyphenyl)propan-2-yl]piperidin-4-yl}indoline

A mixture of 1-(piperidin-4-yl)indoline (300 mg),3,4-dimethoxyphenylacetone (870 mg), sodium cyanoborohydride (280 mg)and molecular sieve (1.0 g) in methanol (20 ml) was stirred at roomtemperature for 3 days. Then the reaction solution was filtered andconcentrated under reduced pressure, water and ethyl acetate were addedthereto and the layers were separated. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and purified by silica gelcolumn chromatography (methylene chloride/ethanol system) followed byconversion into a hydrochloride in a conventional manner. Thus thehydrochloride (220 mg) of the title compound was obtained as a whitepowder (yield: 35%).

m.p. (hydrochloride): 245° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.00(3H, d, J=7 Hz), 1.82-1.91(2H, m), 2.01-2.13(2H, m),2.55-2.63(1H, m), 2.88(2H, t, J=8 Hz), 3.17-3.28(4H, m), 3.43-3.61(4H,m), 3.71(3H, s), 3.74(3H, s), 3.76-3.83(1H, m), 6.52-6.56(2H, m),6.75-6.78(1H, m), 6.87-6.90(2H, m), 6.98-7.03(2H, m), 9.90(1H, br-s).

FAB-Mass: 381(MH+).

Example 77: Synthesis of1-{1-[(1,4-benzodioxan-2-yl)methyl]piperidin-4-yl}indoline

1-(4-Piperidyl)indoline (303 mg) and 2-bromoethyl-1,4-benzodioxane (344mg) were treated as in Example 2 to give the hydrochloride (372 mg) ofthe title compound as beige crystals (yield: 67%).

m.p. (hydrochloride): 200-205° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.88(2H, d, J=12.4 Hz), 2.10-2.25(2H, m), 2.92(2H, t, J=8.4 Hz),3.13-3.58(7H, m), 3.72-3.82(2H, m), 4.05(1H, dd, J=11.4 Hz, 6.8 Hz),4.34(1H, dd, J=11.4 Hz, 2 Hz), 4.90-4.95(1H, m), 6.67(1H, d, J=6.8 Hz),6.68(1H, dd, J=6.8 Hz, 6.6 Hz), 6.84-6.96(4H, m), 7.04(1H, dd, J=9 Hz,7.6 Hz), 7.08(1H, d, J=7.6 Hz), 11.40(1H, br-s).

ESI-Mass: 351(MH+).

Example 78: Synthesis of1-{1-[3-(3,4-methylenedioxypheoxy)propyl]piperidin-4-yl}indoline

1-(4-Piperidyl)indoline (303 mg) and3-bromopropoxy-1,2-methylenedioxybenzene (389 mg) were treated as inExample 2 to give the hydrochloride (443 mg) of the title compound aspale blue crystals (yield: 73%).

m.p. (hydrochloride): 210-212° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.84(2H, d, J=11.6 Hz), 1.98-2.18(4H, m), 2.88(2H, t, J=8.4 Hz),3.05(2H, q, J=11.6 Hz), 3.11-3.20(2H, m), 3.30(2H, t, J=8.4 Hz),3.57(2H, d, J=11.6 Hz), 3.72(1H, m), 3.97(2H, t, J=6 Hz), 5.94(2H, s),6.37(1H, dd, J=8.4 Hz, 2.8 Hz), 6.54(1H, d, J=7.6 Hz), 6.57(1H, t, J=7.6Hz), 6.63(1H, d, J=2.8 Hz), 6.80(1H, d, J=8.4 Hz), 6.99(1H, t, J=7.6Hz), 7.02(1H, d, J=7.6 Hz), 10.45(1H, br-s).

ESI-Mass: 381(MH+).

Example 79: Synthesis ofcis-1-[1-(4-fluorophenethyl)-3-methylpiperidin-4-yl]indoline

Indoline (238 mg), 1-[2-(4-fluorophenyl)ethyl]-3-methyl-4-piperidone(588 mg) obtained in Production Example 40-5 and triacetoxylated sodiumborohydride (1.19 g) were treated as in Example 101 to give the titlecompound (100 mg) as a yellow oil (yield: 15%).

m.p. (oxalate): 229-230° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.09(3H, d, J=6.5 Hz), 1.69(1H, m), 2.10(2H, m), 2.26(1H, br-d),2.30(1H, m), 2.47(1H, m), 2.56(1H, m), 2.74(2H, m), 2.81(1H, br-d),2.98(3H, m), 3.42(1H, m), 3.56(1H, q, J=9.0 Hz), 3.64(1H, m),6.31(1H,br-d), 6.54(1H, br-t),6.96(2H, br-d), 7.03(2H, m), 7.17(2H, m).

FAB-Mass: 339(MH+).

Example 80-1: Synthesis of 1-benzyl-3-hydroxymethyl-4-piperidone

(80-1-1) Ethyl 1-benzyl-4,4-ethylenedioxy-3-piperidinecarboxylate

p-Toluenesulfonic acid monohydrate (1.5 g) was added to a solution (600ml) of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate (CAS Registry No.1454-53-1, 44.7 g) and ethylene glycol (100 ml) in toluene and theresultant mixture was heated under reflux overnight. After cooling themixture to room temperature, ice water (500 ml) and a saturated aqueoussolution (300 ml) of sodium bicarbonate were added thereto followed byextraction with ethyl acetate (400 ml) for three times. The organicphase was washed successively with water (200 ml) twice and brine (300ml) and dried over anhydrous magnesium sulfate. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (30.4 g) as a yellow oil (yield: 66%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.22(3H, t, J=6.0 Hz), 1.74(1H, m), 1.98(1H, m), 2.48(1H, m),2.68(2H, m), 2.82(2H, m), 3.49(1H, d, J=11.0 Hz), 3.57(1H, d, J=11.0Hz), 3.89(1H, d, J=7.0 Hz), 3.96(3H, m), 4.13(2H, q, J=6.0 Hz),7.22-7.32(5H, m).(80-1-2) 1-Benzyl-4,4-ethylenedioxy-3-piperidinemethanol

In a stream of nitrogen, lithium aluminum hydride (702 mg) was carefullyadded to ice cooled dry tetrahydrofuran (100 ml). Into the resultantmixture was slowly added dropwise a solution of ethyl1-benzyl-4,4-ethylenedioxy-3-piperidinecarboxylate (4.58 g) obtainedabove in tetrahydrofuran (30 ml). The resultant mixture was graduallyheated and further stirred at room temperature overnight. Under icecooling, water (0.7 ml), a 5 N aqueous solution (2.1 ml) of sodiumhydroxide and further water (2.1 ml) were successively added to thereaction mixture carefully. Next, the resulting mixture was dried overanhydrous sodium sulfate and filtered through celite followed byconcentration under reduced pressure. Thus the title compound (4.03 g)was obtained as a colorless oil (yield: 100%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.67(1H, m), 1.92(1H, m), 2.01(1H, m), 2.43-2.66(3H, m), 2.70(1H,br-d), 3.49(2H, s), 3.77(1H, d, J=11.0 Hz), 3.83(1H, d, J=11.0 Hz),3.96(4H, br-s), 7.23-7.33(5H, m).(80-1-3) 1-Benzyl-3-hydroxymethyl-4-piperidone

1-Benzyl-4,4-ethylenedioxy-3-piperidinemethanol (960 mg) was dissolvedunder ice cooling in a mixed solvent of water (10 ml) and conc. sulfuricacid (6 ml). The resultant mixture was gradually heated to roomtemperature and further stirred for a day. Under ice cooling, a 5 Naqueous solution of sodium hydroxide was added to the mixture to adjustto ca. pH 8. After extracting with chloroform (50 ml) twice, the mixturewas washed successively with water and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give thetitle compound (710 mg) as a colorless oil (yield: 89%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.47(2H, m), 2.60(2H, m), 2.70(1H, m), 3.01(2H, m), 3.62(2H, s),3.71(1H, dd, J=7.5 Hz, 13.5 Hz), 3.76(1H, br-d), 7.25-7.37(5H, m).Example 80-2: Synthesis ofcis-1-(1-benzyl-3-hydroxymethylpiperidin-4-yl)indoline

Indoline (238 mg), 1-benzyl-3-hydroxymethyl-4-piperidone (548 mg) andtriacetoxylated sodium borohydride (1.19 g) were treated as in Example 1to give the title compound (140 mg) as a yellow powder (yield: 22%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.79(1H, br-d), 2.08(1H, br-s), 2.14(1H, dt, J=2.8 Hz, 12.0 Hz),2.49(1H, br-d), 2.54(1H, dt, J=4.5 Hz, 12.0 Hz), 3.02(3H, m), 3.14(1H,br-d), 3.49(1H, d, J=12.0 Hz), 3.55(1H, d, J=12.0 Hz), 3.56(1H, t,J=12.5 Hz), 3.64(1H, q, J=9.0 Hz), 3.82(2H, m), 3.97(1H, br-d), 6.28(1H,d, J=7.5 Hz), 6.56(1H, t, J=7.5 Hz), 7.00(1H, t, J=7.5 Hz), 7.04(1H, d,J=7.5 Hz), 7.27-7.37(5H, m).

Example 81-1: Synthesis of cis-1-(3-acetoxymethylpiperidin-4-yl)indoline

(81-1-1) cis-1-(1-Benzyl-3-acetoxymethylpiperidin-4-yl)-indoloine

Under ice cooling, triethylamine (111 mg) and acetyl chloride (86 mg)were added to a solution ofcis-1-(1-benzyl-3-hydroxymethylpiperidin-4-yl)indoline (322 mg) intetrahydrofuran (3 ml). The resultant mixture was stirred under icecooling for 30 min and then at room temperature for additional 1 hr.Then ethyl acetate (15 ml) was added thereto followed by filtrationthrough celite. After removing the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound (340 mg) as a yellow oil(yield: 93%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.76(1H, br-d), 1.83(3H, s), 1.99-2.20(3H, m), 2.44(1H, m),2.92-3.03(4H, m), 3.40(1H, d, J=13.0 Hz), 3.48-3.56(3H, m), 3.58(1H, d,J=13.0 Hz), 4.13(1H, dd, J=4.2 Hz, 10.0 Hz), 4.63(1H, t, J=10.0 Hz),6.31(1H, d, J=7.5 Hz), 6.57(1H, t, J=7.5 Hz), 7.02(2H, m), 7.21-7.31(5H,m).(81-1-2) cis-1-(3-Acetoxymethylpiperidin-4-yl)indoline

Under ice cooling, a solution of 1-chloroethyl chloroformate (135 mg) indichloroethane (1 ml) was added to a solution ofcis-1-(1-benzyl-3-acetoxymethylpiperidin-4-yl)indoline (340 mg) indichloroethane (5 ml). After stirring for 30 min, the mixture was heatedunder reflux for 1 hr. Then, it was cooled and concentrated underreduced pressure. After adding methanol (10 ml) thereto, the mixture wasstirred at 50° C. for 10 min and heated under reflux for 30 min. Then itwas cooled to room temperature again and concentrated under reducedpressure. After adding a saturated aqueous solution (10 ml) of sodiumbicarbonate, the mixture was extracted with chloroform (15 ml) for threetimes. The organic phase was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give the title compound (290 mg)as a yellow powder (yield: 100%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.94(1H, dd, J=4.5 Hz, 13.0 Hz), 1.99(3H, s), 2.45(1H, m),2.79(1H, dt, J=3.0 Hz, 12.0 Hz), 2.87(1H, dd, J=3.0 Hz, 12.5 Hz),2.97(3H, m), 3.19(1H, br-d), 3.26(1H, br-d, J=13.5 Hz), 3.55(2H, t,J=9.0 Hz), 3.64(1H, td, J=5.0 Hz, 12.5 Hz), 4.20(1H, dd, J=4.5 Hz, 11.5Hz), 4.56(1H, t, J=10.5 Hz), 6.34(1H, d, J=7.5 Hz), 6.58(1H, t, J=7.5Hz), 7.03(2H, m).

Example 81-2 Synthesis ofcis-1-[1-(4-fluorophenethyl)-3-hydroxymethylpiperidin-4-yl]indoline

(81-2-1)cis-1-[1-(4-Fluorophenethyl)-3-acetoxymethyl-piperidin-4-yl]indoline

cis-1-(3-Acetoxymethylpiperidin-4-yl)indoline (280 mg) was dissolved indimethylformamide (4 ml) and methanol (1 ml). To the resultant solutionwere added triethylamine (222 mg) and 4-fluorophenethyl bromide (285 mg)followed by stirring at 50° C. for 2 hr. Then the reaction mixture wascooled and water (50 ml) was added thereto. After extracting with ether(50 ml) twice, the organic phase was washed with water (20 ml) twice anda 2 N aqueous solution (50 ml) of sodium hydroxide once and dried overanhydrous magnesium sulfate. Then the solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(100 mg) as a colorless oil (yield: 28%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.77(1H, br-d), 1.93(3H, s), 1.98(1H, dd, J=4.0 Hz, 12.0 Hz),2.12-2.21(2H, m), 2.42-2.63(4H, m), 2.73(2H, m), 2.98(2H, m), 3.06(1H,br-d), 3.46-3.58(3H, m), 4.20(1H, dd, J=3.5 Hz, 10.0 Hz), 4.46(1H, t,J=9.5 Hz), 6.33(1H, d, J=7.5 Hz), 6.58(1H, t, J=7.5 Hz), 6.96(2H, br-t),7.04(2H, br-d), 7.15(2H, m).(81-2-2)cis-1-[1-(4-Fluorophenethyl)-3-hydroxymethylpiperidin-4-yl]indoline

Potassium carbonate (130 mg) was added to a solution ofcis-1-[1-(4-fluorophenethyl)-3-acetoxymethylpiperidin-4-yl]indoline (100mg) obtained above in methanol (6 ml) and the resultant mixture wasstirred at room temperature for 4 hr. After adding ether (20 ml), themixture was filtered through celite and the filtrate was concentratedunder reduced pressure. Ethyl acetate (20 ml) was added to the residuefollowed by filtration again. Then the filtrate was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(40 mg) as a pale yellow powder (yield: 45%).

m.p. (oxalate): 173-174° C.

¹H-NMR (400 MHz, CDCl₃):

1.82(1H, br-d), 2.08(1H, br-s), 2.18(1H, t, J=11.0 Hz), 2.50(2H, m),2.59(2H, t, J=7.5 Hz), 2.80(2H, br-t), 3.01(2H, m), 3.16(2H, m),3.57(1H, m), 3.64(1H, q, J=9.0 Hz), 3.82(2H, m), 3.94(1H, d, J=10.5 Hz),6.27(1H, d, J=7.5 Hz), 6.55(1H, t, J=7.5 Hz), 6.96-7.06(4H, m), 7.14(2H,m).

FAB-Mass: 355(MH+).

Example 82: Synthesis oftrans-1-(4-fluorophenethyl)-3-hydroxymethylpiperidin-4-yl]indoline

(82-1) trans-1-(1-Acetyl-3-hydroxymethylpiperidin-4-yl)indoline

To a solution oftrans-1-(1-acetyl-3-ethoxycarbonyl-piperidin-4-yl)indoline (780 mg) inethanol (40 ml) was added sodium borohydride (5.7 g) in 3 portions at 30min. intervals. After stirring at room temperature overnight, sodiumborohydride (3.3 g) was added thereto and the resultant mixture wasstirred for additional 4 hr. Then ethyl acetate (20 ml) and water (50ml) were successively added carefully to the reaction mixture followedby extraction with ethyl acetate (50 ml) for three times. The organicphase was washed with water (100 ml) twice and brine once, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (methylenechloride/methanol system) to give the title compound (250 mg) as ayellow powder (yield: 39%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.60(1H, m), 1.72(1H, m), 1.97(1H, m), 2.11(3H of 1tautomer, s),2.14(3H of 1tautomer, s), 2.51(2H, m), 2.92-3.15(3H, m), 3.28(1H, m),3.38-3.81(4H, m), 3.89(1H of 1tautomer, br-d), 3.99(1H of 1tautomer,br-d), 4.75(1H, br-d), 6.50(1H, m), 6.67(1H, m), 7.05(2H, m).(82-2) trans-1-(3-Hydroxymethylpiperidin-4-yl) indoline

Sodium hydroxide (220 mg) was added to a solution oftrans-1-(1-acetyl-3-hydroxymethylpiperidin-4-yl)indoline (250 mg) inethanol (10 ml)-water (0.5 ml) mixtures and the resultant mixture washeated under reflux for 20 hr. After cooling and adding water (50 ml),the resultant mixture was extracted with chloroform (30 ml) for threetimes. The organic phase was washed successively with water (50 ml) andbrine (50 ml), dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to give the title compound (190 mg) as acolorless oil (yield: 85%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.56-1.69(2H, m), 1.95-2.07(1H, m), 2.46(1H, t, J=11.5 Hz),2.64(1H, dt, J=2.5 Hz, 11.5 Hz), 2.95(2H, m), 3-17(2H, m), 3.34(1H,br-q), 3.42(1H, dt, J=4.5 Hz, 10.5 Hz), 3.50(1H, dt, J=5.0 Hz, 8.5 Hz),3.61(1H, dd, J=5.0 Hz, 11.0 Hz), 3.67(1H, dd, J=5.0 Hz, 11.0 Hz),6.53(1H, d, J=7.5 Hz), 6.66(1H, t, J=7.5 Hz), 7.06(2H, m).(82-3)trans-1-[1-(4-Fluorophenethyl)-3-hydroxymethylpiperidin-4-yl]indoline

trans-1-(3-Hydroxymethylpiperidin-4-yl)indoline (190 mg) was reactedwith triethylamine (152 mg) and 4-fluorophenethyl bromide (406 mg) as inExample 2 to give the title compound (210 mg) as a brown oil (yield:72%).

m.p. (oxalate): 113-116° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.69(1H, m), 1.79(1H, m), 1.92(1H, t, J=11.0 Hz), 2.07(1H, br-t),2.17(1H, m), 2.58(2H, br-t), 2.79(2H, br-t), 2.95(2H, m), 3.06(1H,br-d), 3.13(1H, br-d), 3.35(2H, m), 3.49(1H, m), 3.64(1H, dd, J=4.5 Hz,11.0 Hz), 3.71(1H, dd, J=6.0 Hz, 11.0 Hz), 6.52(1H, d, J=7.5 Hz),6.67(1H, t, J=7.5 Hz), 6.97(2H, t, J=8.0 Hz), 7.07(2H, br-t), 7.15(2H,m).

FAB-Mass: 355(MH+).

Example 83: Synthesis of1-[2-(4-acetamidomethylphenyl)ethyl]-4-(indan-1-yl)piperidin-1-oxide

1-[1-(4-Acetoamidomethylphenethyl)piperidin-4-yl]-indoline (0.50 g)obtained in Example 36 was dissolved in methylene chloride (20 ml) and70% m-chloroperbenzoic acid (0.37 g) was added thereto at 0° C. Thereaction solution was stirred at room temperature for 30 min followed bythe addition of sodium carbonate (5.0 g). The reaction mixture was filtered through alumina and washed with a mixture of methylene chlorideand methanol (10:1). After concentrating the filtrate under reducedpressure, the resulting residue was purified by silica gel columnchromatography (methylene chloride/methanol system) to give the titlecompound (0.15 g) as a white powder (yield: 28.8%).

m.p.: 130-131° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.77(2H, br-d), 2.03(3H, s), 2.50-2.73(5H, m), 2.97(2H, t, J=8.0Hz), 3.16-3.26(3H, m), 3.36-3.60(5H, m), 4.40(2H, d, J=9.6 Hz), 6.32(1H,m), 6.41(1H, d, J=8.0 Hz), 6.65(1H, t, J=7.6 Hz), 7.04(1H, t, J=7.6 Hz),7.08(1H, d, J=7.2 Hz), 7.19(2H, d, J=8.0 Hz), 7.23(2H, d, J=8.0 Hz).

FAB-Mass: 394(MH+).

Example 84: Synthesis ofcis-1-[1-ethyl-3-(4-fluorophenoxymethyl)piperidin-4-yl]indoline

Under a nitrogen gas stream, 4-fluorophenol (168 mg) andtriphenyiphosphine (420 mg) were added to a solution ofcis-1-(1-ethyl-3-hydroxymethylpiperidin-4-yl)indoline (300 mg) intetrahydrofuran (4 ml). After cooling the resultant mixture to −10° C.,diethyl azodicarboxylate (278 mg) was gradually added dropwisethereinto. Then the resultant mixture was gradually warmed to roomtemperature and stirred at the same temperature overnight. After addingwater (40 ml), the reaction mixture was extracted with ether (40 ml) forthree times. The organic phase was washed successively with a saturatedaqueous solution (40 ml) of sodium bicarbonate and a 1 N aqueoussolution (40 ml) of sodium hydroxide, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia Chemical Ltd.NH-DM2035, hexane/ethyl acetate system) to give the title compound (100mg) as a colorless oil (yield: 25%).

m.p. (oxalate): 97-98° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.04(3H, t, J=7.0 Hz), 1.82(1H, m), 2.00(1H, dq, J=3.5 Hz, 11.5Hz), 2.11(2H, m), 2.35(1H, m), 2.44(1H, m), 2.62(1H, m), 2.98(3H, m),3.17(1H, br-d, JJ=10.5 Hz), 3.54(3H, m), 4.10(1H, dd, J=3.5 Hz, 8.0Hz),4.34(1H, t, J=8.5 Hz), 6.38(1H, d, J=7.5 Hz), 6.59(1H, t, J=7.5 Hz),6.77(2H, m), 6.88(2H, br-t), 7.01-7.06(2H, m).

FAB-Mass: 355(MH+).

Example 85-1: Synthesis of ethyl 1-acetyl-4-oxo-3-piperidinecarboxylate

(85-1-1) Ethyl 4-oxo-3-piperidinecarboxylate hydrochloride

10% palladium/active carbon (2 g) was added to a solution of ethyl1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride (30 g) in methanol(500 ml) and the resultant mixture was stirred at room temperature underhydrogen atmosphere for a day. After filtering the reaction mixturethrough celite, the filtrate was concentrated under reduced pressure togive the title compound (20.0 g) as a white powder (yield: 97%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.30(3H, t, J=6.0 Hz), 2.66(2H, t, J=5.5 Hz), 3.42(2H, t, J=5.5Hz), 3.84(2H, s), 4.29(2H, q, J=6.0 Hz).(85-1-2) Ethyl 1-acetyl-4-oxo-3-piperidinecarboxylate

Ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride (20.0 g)obtained above was dissolved in pyridine (150 ml). To the resultantsolution was added acetic anhydride (10.2 g) at room temperature over 5min or longer and the resultant mixture was stirred at room temperaturefor 2 hr. After adding ethyl acetate (500 ml), the reaction mixture wasfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography (ethylacetate/methanol system) to give the title compound (19.9 g) as a whitepowder (yield: 97%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) mixture of tautomers

major: 1.34(3H, t, J=6.0 Hz), 2.16(3H,s), 2.39(2H, t, J=5.5 Hz),3.75(2H, t, J=5.5 Hz), 4.10(2H, s), 4.28(2H, q, J=6.0 Hz), 12.08(1H,s).

minor: 1.32(3H, t, J=6.0 Hz), 2.15(3H, s), 2.44(2H, t, J=5.5 Hz),3.60(2H, t, J=5.5 Hz), 4.23(2H, s), 4.26(2H, q, J=6.0 Hz), 12.06(1H, s).

Example 85-2: Synthesis ofcis-1-(1-acetyl-3-ethoxycarbonylpiperidin-4-yl)indoline

Indoline (12.5 g), ethyl 1-acetyl-4-oxo-3-piperidinecarboxylate (22.3 g)and triacetoxylated sodium borohydride (48.7 g) were treated as inExample 1 to give the title compound (7.12 g) as a pale yellow powder(yield: 22%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) mixture of tautomers 1.19(3H of 1tautomer, t, J=6.0 Hz), 1.21(3Hof 1tautomer, t, J=6.0 Hz), 2.07(3H of 1tautomer, s), 2.14(3H of1tautomer, s), 2.36-3.07(5H, m), 3.19-3.62(3H, m), 3.75(1H of 1tautomer,m), 3.93-4.13(3H, m), 4.66(1H of 1tautomer, br-d), 4.82(1H of 1tautomer,br-d), 6.34(1H, d, J=7.5 Hz), 6.61(1H, t, J=7.5 Hz), 7.05(2H, m).Example 85-3: Synthesis oftrans-1-(1-acetyl-3-ethoxycarbonylpiperidin-4-yl)indoline

Potassium carbonate (138 mg) was added to a solution (150 ml) of cis-1-(1-acetyl-3-ethoxycarbonylpiperidin-4-yl)indoline (4.35 g) in ethanoland the resultant mixture was stirred at 60° C. for a day followed byconcentration under reduced pressure. Ethyl acetate (200 ml) was addedto the residue, which was then washed successively with water (50 ml)once and brine (50 ml) once, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Thus the title compound (4.22 g)was obtained as a yellow oil (yield: 97%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) mixture of tautomers 1.11(3H, t, J=6.0 Hz), 1.59(1H, m), 1.71(1H,m), 2.13(3H of 1tautomer, s), 2.14(3H of 1tautomer, s), 2.61-2.82(2H,m), 2.95(2H, m), 3.22(1H, m), 3.34(1H, m), 3.54(1H, m), 3.93(2H, m),3.99(2H, m), 4.77(1H of 1 tautomer, br-d), 4.88(1H of 1 tautomer, br-d),6.45(1H, m), 6.61(1H, br-t), 7.03(2H, br-t).

Example 85-4: Synthesis oftrans-1-[1-ethyl-3-(4-fluorobenzyloxymethyl)piperidin-4-yl]indoline

(85-4-1) trans-1-(1-Ethyl-3-hydroxymethylpiperidin-4-yl)indoline

In a stream of nitrogen, lithium aluminum hydride (133 mg) was carefullyadded to dry tetrahydrofuran (5 ml) under ice cooling. To the resultantmixture was gradually added a solution oftrans-1-(1-acetyl-3-ethoxycarbonylpiperidin-4-yl)indoline (850 mg) indry tetrahydrofuran (5 ml) and the resulting mixture was stirred at 0°C. overnight. Under ice cooling and vigorous stirring, water (0.13 ml),a 5 N aqueous solution (0.13 ml) of sodium hydroxide and further water(0.4 ml) were successively added thereto. After allowing to warm theresultant mixture to room temperature, ethyl acetate (30 ml) was addedthereto followed by drying over anhydrous sodium sulfate. Afterfiltering and concentrating under reduced pressure, the resultingresidue was purified by silica gel column chromatography (methylenechloride/methanol system) to give the title compound (340 mg) as a paleyellow powder (yield: 49%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.11(3H, t, J=6.0 Hz), 1.68(1H, m), 1.79(2H, m), 1.96(1H, dt,J=2.5 Hz, 11.0 Hz), 2.17(1H, m), 2.44(2H, q, J=6.0 Hz), 2.95(2H, m),3.05(2H, m), 3.34(2H, m), 3.48(1H, dt, J=5.0 Hz, 8.0 Hz), 3.63(1H, dd,J=5.0 Hz, 10.0 Hz), 3.69(1H, dd, J=5.5 Hz, 10.5 Hz), 6.51(1H, d, J=7.5Hz), 6.65(1H, t, J=7.5 Hz), 7.06(2H, m).(85-4-2)trans-1-[1-Ethyl-3-(4-fluorobenzyloxymethyl)piperidin-4-yl]indoline

To a suspension of 55% sodium hydride (83 mg) in dimethylf ormamide (3ml) were added under ice cooling a solution oftrans-1-(1-ethyl-3-hydroxymethylpiperidin-4-yl)indoline (340 mg) indimethylformamide (2 ml) and 4-fluorobenzyl bromide (378 mg). Theresulting mixture was gradually warmed to room temperature and thenstirred at the same temperature overnight. After adding water (50 ml),it was extracted with ethyl acetate (50 ml) thrice. The organic phasewas washed with water (50 ml) once and then with brine (50 ml) once,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. Next, the residue was purified by silica gelcolumn-chromatography (Fuji Silysia Chemical Ltd. NH-DM2035,hexane/ethyl acetate system) to give the title compound (50 mg) as acolorless oil (yield: 10%).

m.p. (oxalate): 177-178° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.11(3H, t, J=6.0 Hz), 1.73(1H, m), 1.96(2H, m), 2.15(1H, m),2.45(2H, q, J=6.0 Hz), 2.83-2.97(2H, m), 3.04(1H, m), 3.23(1H, br-d),3.32(3H, m), 3.57(1H, dd, J=2.5 Hz, 9.0 Hz), 4.35(1H, d, J=11.5 Hz),4.41(1H, d, J=11.5 Hz), 4.50(2H, s), 6.37(1H, d, J=7.5 Hz), 6.57(1H, t,J=7.5 Hz), 6.95(2H, br-t), 7.02(2H, m), 7.22(2H, dd, J=6.0 Hz, 9.0 Hz).

FAB-Mass: 369(MH+).

Example 86: Synthesis ofcis-1-[1-ethyl-3-(4-fluorobenzyloxymethyl)piperidin-4-yl]indoline

(86-1) cis-1-1(-Ethyl-3-acetoxymethylpiperidin-4-yl)indoline

Triethylamine (1.21 g) and ethyl iodide (1.72 g) were added to asolution of cis-1-(3-acetoxymethylpiperidin-4-yl)indoline (3.53 g) indimethylf ormamide (40 ml) followed by stirring the mixture at 50° C.for 4 hr. Under ice cooling, water (150 ml) was added to the reactionmixture, which was then extracted with ethyl acetate (100 ml) for threetimes. The organic phase was washed with water (50 ml) twice and brine(100 ml) once, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methanol system) to give the titlecompound (2.06 g) as a pale yellow oil (yield: 63%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.04(3H, t, J=7.0 Hz), 1.77(1H, m), 1.92(3H, s), 1.96-2.11(3H,m), 2.31-2.48(3H, m), 2.93-3.03(4H, m), 3.49(1H, m), 3.56(2H, m),4.22(1H, dd, J=4.5 Hz, 10.5 Hz), 4.47(1H, dd, J=9.0 Hz, 10.0 Hz),6.32(1H, d, J=7.5 Hz), 6.56(1H, t, J=7.5 Hz), 7.02(2H, m).(86-2) cis-1-(1-Ethyl-3-hydroxymethylpiperidin-4-yl)indoline

Potassium carbonate (3.0 g) was added to a solution ofcis-1-(1-ethyl-3-acetoxymethylpiperidin-4-yl)indoline-(2.06 g) inmethanol (120 ml) and the resultant mixture was stirred at roomtemperature for 4 hr. After adding ether (80 ml), the mixture wasfiltered through celite and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Fuji Silysia Chemical Ltd. NH-DM2035, hexane/ethyl acetate system) togive the title compound (1.19 g) as a pale yellow powder (yield: 67%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.11(3H, t, J=7.0 Hz), 1.82(1H, br-d), 2.06(1H, m), 2.11(1H, dd,J=3.0 Hz, 11.5 Hz), 2.40(2H, q, J=7.0 Hz), 2.41(1H, m), 2.52(1H, m),3.01(2H, m), 3.10(1H, m), 3.16(1H, td, J=2.0 Hz, 11.5 Hz), 3.56(1H, td,J=5.0 Hz, 12.0 Hz), 3.66(1H, q, J=9.0 Hz), 3.82(1H, dd, J=6.0 Hz, 9.0Hz), 3.87(1H, br-d), 3.98(1H, td, J=2.0 Hz, 11.5 Hz), 6.27(1H, d, J=7.5Hz), 6.55(1H, t, J=7.5 Hz), 7.00(1H, br-t), 7.04(1H, br-d).(86-3) cis-1-[1-Ethyl-3-(4-fluorobenzyloxymethyl)piperidin-4-yl]indoline

To a suspension of 65% sodium hydride (42 mg) in dimethylformamide (3ml) were added under ice cooling a solution ofcis-1-(1-ethyl-3-hydroxymethylpiperidin-4-yl)indoline (250 mg) indimethylformamide (1 ml) and 4-fluorobenzyl bromide (264 mg). Then thereaction mixture was gradually warmed to room temperature and stirred atthe same temperature overnight. After adding ice water (30 ml), theresultant mixture was extracted with ethyl acetate (30 ml) for threetimes. The organic phase was washed with water (50 ml) once and thenwith brine (50 ml) once, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Fuji Silysia Chemical Ltd. NH-DM2035,hexane/ethyl acetate system) to give the title compound (100 mg) as apale brown amorphous solid (yield: 28%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.07(3H, t, J=7.0 Hz), 1.75(1H, m), 1.94(1H, m), 2.07(1H, m),2.31-2.54(3H, m), 2.94(3H, m), 3.15(1H, br-d), 3.48(2H, m), 3.62(1H, dd,J=4.0 Hz, 8.0 Hz), 3.86(1H, m), 4.18(1H, d, J=4.0 Hz), 4.41(1H, d, J=4.0Hz), 6.36(1H, d, J=7.5 Hz), 6.57(1H, t, J=7.5 Hz), 6.95(2H, br-t),7.00-7.06(2H, m), 7.20(2H, dd, J=6.0 Hz, 9.0 Hz).

FAB-Mass: 369(MH+).

Example 87: Synthesis of1-(1-acetylpiperidin-4-yl)indoline-7-carbaldehyde

(87-1) 1-(1-Acetylpiperidin-4-yl)indoline

Indoline (25 ml), 1-acetyl-4-piperidone (25 g) and glacial acetic acid(20 ml) were dissolved in methanol (300 ml). After adding 10% palladiumcarbon (1.0 g) thereto, catalytic reduction was carried out underatmospheric pressure. After the completion of the reaction, the reactionsolution was filtered through celite, washed with methanol andconcentrated under reduced pressure. The residue was partitioned betweenwater and ethyl acetate and basified with a 5 N aqueous solution ofsodium hydroxide followed by extraction with ethyl acetate. The ethylacetate layer was washed with water and brine, dried and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane system) to give the titlecompound (35.6 g) as a pale yellow wax (yield: 82.2%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.50-1.62(2H, m), 1.81-1.93(2H, m), 2.12(3H, s), 2.59(1H, br-t),2.96(2H, t, J=7.2 Hz), 3.15(1H, br-t), 3.31-3.39(2H, m), 3.57-3.64(1H,m), 3.93(1H, br-d), 4.78(1H, br-d), 6.42(1H, d, J=8.0 Hz), 6.62(1H, t,J=8.0 Hz), 7.02-7.09(2H, m).(87-2) 1-(4-Piperidin-1-yl)indoline

1-(1-Acetylpiperidin-4-yl)indoline (24.4 g) obtained in the above (87-1)was dissolved in ethanol (500 ml). To the resultant solution was added a5 N aqueous solution (80 ml) of sodium hydroxide followed by heatingunder reflux for 5 hr. Then the reaction solution was concentrated underreduced pressure and the residue was partitioned between water and ethylacetate. The ethyl acetate layer was washed with brine, dried andconcentrated under reduced pressure. The residue was purified byNH-silica gel column chromatography (ethyl acetate) to give the titlecompound (15.9 g) as a flesh-colored wax (yield: 78.7%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.53-1.65(2H, m),1.77-1.85(2H, m), 2.68(2H, br-t), 2.95(2H, t,J=7.2 Hz), 3.16-3.22(1H, m), 3.39(2H, t, J=7.2 Hz), 3.40-3.50(1H, m),6.41(1H, d, J=8.0 Hz), 6.59(1H, t, J=8.0 Hz), 7.01-7.07(2H, m).(87-3) 1-(1-Acetylpiperidin-4-yl)indoline-7-carbaldehyde

Phosphorus oxychloride (4.60 g) was added dropwise into ice cooled DMF(40 ml) followed by stirring for 15 min. Next,1-(1-acetylpiperidin-4-yl)indoline (7.32 g) obtained in the above (87-1)was added thereto. The reaction solution was heated at 80° C. for 3 hrwith vigorous stirring. After cooling, the reaction solution was partiti oned between ethyl acetate and water. The ethyl acetate layer waswashed with water and brine, dried and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (ethyl acetate) to give the title compound (3.2 g) as apale yellow oil (yield: 39.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.62(2H, br-q), 1.81-1.92(2H, m), 2.12(3H, s), 2.61(1H, br-t),3.04(2H, t, J=7.2 Hz), 3.16(1H, br-t), 3.50-3.60(2H, m), 3.66-3.75(1H,m), 3.95(1H, br-d), 4.81(1H, br-d), 6.40(1H, d, J=8.0 Hz), 7.53-7.59(2H,m), 9.66(1H, s).

Example 88: Synthesis of1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-bromoindoline

Triacetoxylated sodium borohydride (11.7 g) was added to a mixture of 6-bromoindoline (8.3 g), 1-(t-butoxycarbonyl)-4-piperidone (10 g, [CASRegistry No. 7909-07-3]), acetic acid (14.9 g) and dichloroethane (200ml) followed by stirring overnight. Then the reaction solution wasconcentrated under reduced pressure, and the pH value thereof wasadjusted to 9 with ethyl acetate, an 8 N aqueous solution of sodiumhydroxide and water and the layers were separated. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (10.3 g) (yield: 64%).

δ(ppm) 1.48(9H, s), 1.50-1.62(2H, m), 1.75-1.82(2H, m), 2.71-2.82(2H,m), 2.90(2H, t, J=8 Hz), 3.40-3.50(1H, m), 3.42(2H, t, J=8 Hz),4.17-4.32(2H, m), 6.52(1H, br-s), 6.75(1H, d, J=8 Hz), 6.90(1H, d, J=8Hz).

Example 89: Synthesis of1-[1-(t-butoxycarbonyl)-piperidin-4-yl]-6-hydroxymethylindoline

A 2.5 M solution (16 ml) of n-butyllithium in hexane was added dropwiseat ±78° C. into a solution of1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-bromoindoline (10 g) intetrahydrofuran (250 ml) over 5 mm. After 10 mm, dimethylformamide (3.0ml) was added and the resultant mixture was allowed to warm to roomtemperature. Next, a saturated aqueous solution of ammonium chloride andethyl acetate were added thereto and the layers were separated. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. To the residue wereadded ethanol (50 ml) and sodium borohydride (1.0 g) and the resultantmixture was stirred at room temperature for 30 mm. Then ice water andethyl acetate were added to the reaction solution and the layers wereseparated. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound (7.9 g) (yield: 91%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.48(9H, s), 1.50-1.63(2H, m), 1.75-1.83(2H, m), 2.71-2.83(2H,m), 2.91(2H, t, J=8 Hz), 3.39(2H, t, J=8 Hz), 3.50-3.60(1H, m),4.10-4.29(2H, m), 4.31(2H, d, J=6 Hz), 6.49(1H, br-s), 6.61(1H, d, J=8Hz), 7.03(1H, d, J=8 Hz).

Example 90: Synthesis of 1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-aminomethylindoline

Under ice cooling, a solution of diethyl azodicarboxylate (4.6 g) intetrahydrofuran (20 ml) was added dropwise into a solution of1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-hydroxymethylindoline (7.9 g),triphenylphosphine (6.9 g) and phthalimide (3.9 g) in tetrahydrofuran(250 ml) and the resultant mixture was stirred at room temperature for 3hr. After concentrating under reduced pressure, the resulting residuewas purified by silica gel column chromatography (ethyl acetate/hexanesystem). Then hydrazine hydrate (3.6 g) and ethanol (150 ml) were addedthereto followed by healing under reflux for 2 hr. After ice cooling,the resulting crystalline precipitates were filtered off and thefiltrate was concentrated under reduced pressure to give the titlecompound (8.3 g).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.48(9H, s), 1.50-1.60(2H, m), 1.71-1.81(2H, m), 2.72-2.89(2H,m), 2.91(2H, t, J=8 Hz), 3.35(2H, t, J=8 Hz), 3.49-3.60(1H, m), 3.83(2H,s), 4.13-4.29(2H, m), 6.42(1H, br-s), 6.58(1H, d, J=8 Hz), 7.00(1H, d,J=8 Hz).Example 91: Synthesis of 1-(1-benzylpiperidin-4-yl)-6-bromoindoline

Triacetoxylated sodium borohydride (14.6 g) was added to amixture of6-bromoindoline (10 g), 1-benzyl-4-piperidone (9.5 g), acetic acid (12g) and dichloroethane (200 ml) over 5 min followed by stirringovernight. Then the reaction solution was concentrated under reducedpressure, the pH value thereof was adjusted to 10 by dilution with ethylacetate, an 8 N aqueous solution of sodium hydroxide and water and theorganic layer was separated. The organic layer was washed successivelywith water and brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby NH-silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (16.3 g) as a brown oil (yield: 87%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.51-1.60(2H, m), 1.69-1.79(2H, m), 2.01-2.13(2H, m), 2.89(2H, t,J=8 Hz), 2.95-3.03(2H, m), 3.22-3.32(1H, m), 3.40(2H, t, J=8 Hz),3.53(2H, s), 6.44(1H, s), 6.65(1H, t, J=8 Hz), 6.84(1H, t, J=8 Hz),7.22-7.36(5H, m).Example 92-1: Synthesis of 1-(1-benzylpiperidin-4-yl)-6-fluoroindole

A solution of 1-benzyl-4-(3-fluorophenyl)-aminopiperidine (11.7 g)synthesized in accordance with the method of Referential Example 1 ofJP-B 40-6347 and oxalyl chloride (10.5 g) in ether (300 ml) was heatedunder reflux for 2 hr. After concentrating under reduced pressure, theresidue was diluted with methylene chloride (120 ml) and the resultantsolution was added dropwise at 0° C. into a solution of anhydrousaluminum chloride (27 g) in methylene chloride (100 ml). After stirringfor 1 hr, the reaction solution was carefully added to a saturatedaqueous solution of sodium bicarbonate. The resulting crystallineprecipitates were filtered off and washed with methylene chloride. Next,the filtrate was pertitioned between two liquid layers. The organiclayer was washed with brine and dried over anhydrous magnesium sulfate.The resulting residue was purified by silica gel column chromatography(hexane/ethyl acetate system) followed by dilution with tetrahydrofuran(200 ml). Into the resultant solution was added dropwise under icecooling a 1 M solution (120 ml) of a borane/tetrahydrofuran complex intetrahydrofuran and the resultant mixture was stirred at roomtemperature overnight followed by heating under reflux for 3 hr. Asaturated aqueous solution of sodium bicarbonate was carefully addeddropwise into the reaction solution, then ethyl acetate was addedthereto and the layers were separated. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was diluted with pyridine (100 ml) andstirred at room temperature for 4 hr. Then a saturated aqueous solutionof sodium bicarbonate and ethyl acetate were added thereto and thelayers were separated. The organic layer was washed with brine and driedover anhydrous magnesium sulfate. The resulting residue was thenpurified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (3.5 g) as a yellow oil (yield: 35%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.00-2.30(6H, m), 3.02-3.18(2H, m), 3.55-3.67(2H, m),4.09-4.19(1H, m), 6.49(1H, s), 6.81-6.89(1H, m), 7.00-7.04(1H, m),7.20(1H, s), 7.22-7.40(5H, m), 7.49-7.56(1H, m).Example 92-2: Synthesis of 1-(1-benzylpiperidin-4-yl)-6-fluoroindoline

Under ice cooling, a 1 M solution (23 ml) of a borane/tetrahydrofurancomplex in tetrahydrofuran was added dropwise into a solution of1-(1-benzylpiperidin-4-yl)-6-fluoroindole (3.5 g) in trif luoroaceticacid (50 ml) followed by stirring for 2 hr. After adding water thereto,the resultant mixture was concentrated under reduced pressure and thenbasified by adding ethanol and a 5 N aqueous solution of sodiumhydroxide followed by stirring for 2 hr. Then a saturated aqueoussolution of sodium bicarbonate and ethyl acetate were added thereto andthe layers were separated. The organic layer was washed with brine anddried over anhydrous magnesium sulfate. The residue was then purified bysilica gel column chromatography (hexane/ethyl acetate system) to givethe title compound (2.0 g) as a brown oil (yield: 57%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.72-1.83(4H, m), 2.89(2H, t, J=8 Hz), 3.00-3.09(2H, m),3.23-3.44(3H, m), 3.42(2H, t, J=8 Hz), 3.52-3.61(2H, m), 6.02-6.09(1H,m), 6.20-6.28(1H, m), 6.89-6.93(1H, m), 7.23-7.40(5H, m).Example 93: Synthesis of 1-(1-benzylpiperidin-4-yl)-6-formylindoline

1-(1-Benzylpiperidin-4-yl)-6-bromoindoline (8.54 g) was dissolved intetrahydrofuran (125 ml). Into the resultant mixture were successivelyadded dropwise in a nitrogen atmosphere a 2.5 M solution (11.5 ml) ofn-butyllithium in n-hexane and N,N-dimethylformamide (6.1 ml) followedby stirring for 2 hr. Then water and ethyl acetate were added theretoand the layers were separated. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(6.360 g) as ayellow oil (yield: 86.1%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.74-1.80(4H, m), 2.11(2H, m), 2.99-3.03(2H, m), 3.01(2H, t,J=8.4 Hz), 3.43(1H, m), 3.47(2H, t, J=8.4 Hz), 3.55(2H, s), 6.82(1H, d,J=1.6 Hz), 7.06(1H, dd, J=1.6, 7.2 Hz), 7.15(1H, d, J=7.2 Hz), 7.28(1H,t, J=4.4 Hz), 7.33(1H, d, J=4.4 Hz), 9.85(1H, s).Example 94: Synthesis of1-(1-benzylpiperidin-4-yl)-6-hydroxyiminomethylindoline

1-(1-Benzylpiperidin-4-yl)-6-formylindoline (6.36 g) was treated as inExample 46 to give the title compound (6.200 g) as a yellow oil (yield:89.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.74-1.89(4H, m), 2.09(2H, dt, J=2.4, 11.6 Hz), 2.91(2H, t, J=8.4Hz), 3.02(2H, br-d), 3.40(1H, m), 3.41(2H, t, J=8.4 Hz), 3.55(2H, s),6.66(1H, s), 6.70(1H, dd, J=1.4, 7.2 Hz), 7.01(1H, d, J=7.2 Hz),7.27(1H, m), 7.32(4H, m), 8.06(1H, s).Example 95: Synthesis of1-(1-benzylpiperidin-4-yl)-6-aminomethylindoline

1-(1Benzylpiperidin-4-yl)-6-hydroxyiminomethylindoline (5.5 g) wastreated as in Example 35 to give the title compound (5.598 g) as a brownoil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.75(4H, m), 2.09(2H, m), 2.10(2H, t, J=8.4 Hz), 3.00(2H, m),3.39(2H, t, J=8.4 Hz), 3.55(2H, s), 3.76(2H, s), 6.36(1H, t, J=0.6 Hz),6.51(1H, dd, J=0.6, 7.2 Hz), 6.99(1H, d, J=7.2 Hz), 7.27(1H, m),7.32(4H, m).Example 96: Synthesis of1-(1-benzylpiperidin-4-yl-6-acetamidomethylindoline

1-(1-Benzylpiperidin-4-yl)-6-aminomethylindoline (5.598 g) and acetylchloride (1.3 ml) were treated as in Example 36 to give the titlecompound (5.598 g) as a brown oil.

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.76(4H, m), 1.99(3H, s), 2.12(2H, m), 2.91(2H, t, J=8.4 Hz),3.02(2H, br-d), 3.36(1H, m), 3.40(2H, t, J=8.4 Hz), 3.57(2H, br-s),4.31(2H, d, J=5.6 Hz), 5.65(1H, m), 6.30(1H, br-d), 6.49(1H, dd, J=1.2,7.4 Hz), 6.98(1H, d, J=7.4 Hz), 7.28(1H, m), 7.35(4H, d, J=8.4 Hz).

ESI-Mass: 364.1.

Example 97: Synthesis of1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-acetamidomethylindoline

1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and4-methoxyphenethyl bromide (240 mg) were treated as in Example 2 to givethe title compound (200 mg) as a white powder (yield: 53%).

m.p.: 151-152° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.50-1.63(2H, m), 1.79-1.81(2H, m), 2.01(3H, s), 2.10-2.30(2H,m), 2.75-2.96(4H, m), 2.93(2H, t, J=8 Hz), 3.10-3.30(2H, m),3.36-3.50(1H, m), 3.44(2H, t, J=8 Hz), 3.79(3H, s), 4.33(2H, d, J=6 Hz),6.47(1H, s), 6.52(1H, d, J=8 Hz), 6.83-6.87(2H, m), 7.00(1H, d, J=8 Hz),7.13-7.16(2H, m).

FAB-Mass: 408(MH+).

Example 98: Synthesis of1-[1-(4-chlorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline

1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and4-chlorophenethyl bromide (240 mg) were treated as in Example 2 to givethe title compound (240 mg) as white scaly crystals (yield: 63%).

m.p.: 151-152° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.50-1.64(2H, m), 1.54-1.90(2H, m), 2.01(3H, s), 2.04-2.34(2H,m), 2.60-3.00(4H, m), 2.93(2H, t, J=8 Hz), 3.06-3.26(2H, m),3.36-3.48(1H, m), 3.43(2H, t, J=8 Hz), 4.33(2H, d, J=6 Hz), 6.38(1H, s),6.51(1H, d, J=8 Hz), 7.00(1H, d, J=8 Hz), 7.11-7.20(2H, m),7.23-7.29(2H, m).

FAB-Mass: 412(MH+).

Example 99: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-5-methoxyindoline

1-(4-Fluorophenethyl)-4-(4-methoxyphenyl)aminopiperidine (10 g)synthesized in accordance with the method of Referential Example 1 ofJP-B 40-6347 was treated as in Example 106 to give the hydrochloride(180 mg) of the title compound as a white powder (yield: 1.4%).

m.p. (hydrochloride): 209-211° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-2.09(4H, m), 2.83-2.96(2H, m), 2.98-3.10(4H, m),3.20-3.29(2H, m), 3.31-3.45(2H, m), 3.60-3.80(3H, m), 3.69(3H, s),4.24-4.34(1H, m), 6.58-6.70(2H, m), 6.75-6.80(1H, m), 7.11-7.20(2H, m),7.29-7.40(2H, m).

FAB-Mass: 355(MH+).

Example 100-1: Synthesis of1-(4-fluorophenethyl)-4-(3-bromophenyl)aminopiperidine

A solution of o-bromoaniline (17.2 g) and 4-fluorophenethylpiperidone(22 g) in toluene (200 ml) was heated under reflux overnight by using aDean-Starke reflux condenser. After concentrating under reducedpressure, the residue was diluted with 1,2-dichloroethane (200 ml) andsodium borohydride (7.6 g) and acetic acid (8.0 g) were added theretofollowed by stirring the resultant mixture at 0° C. for 4 hr. Next, asaturated aqueous solution of sodium bicarbonate and ethyl acetate wereadded to the reaction solution and the layers were separated. Theorganic layer was washed with brine and dried over anhydrous magnesiumsulfate. The residue was purified by silica gel column chromatography(methylene chloride/ethanol system) to give the title compound (10 g) asa brown oil (yield: 27%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.42-1.60(2H, m), 2.02-2.10(2H, m), 2.18-2.25(2H, m),2.55-2.63(2H, m), 2.78-2.84(2H, m), 2.90-3.00(2H, m), 3.23-3.32(1H, m),3.60(1H, d, J=8 Hz), 6.50(1H, d, J=8 Hz), 6.72(1H, s), 6.79(1H, d, J=8Hz), 6.94-7.02(3H, m), 7.12-7.20(2H, m).Example 100-2: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-2,3-dioxo-6-bromoindoline

A solution of 1-(4-fluorophenethyl)-4-(3-bromophenyl)aminopiperidine (10g) and oxalyl chloride (6.7 g) in ether (200 ml) was heated under refluxfor 2 hr. After concentrating under reduced pressure, the residue wasdiluted with methylene chlori de (200 ml) and the resultant solution wasadded dropwise at 0° C. into a solution of anhydrous aluminum chloride(24.7 g) in methylene chloride (60 ml). After stirring for 1 hr, thereaction solution was carefully added to a saturated aqueous solution ofsodium bicarbonate. The resulting crystalline precipitates were filteredoff and washed with methylene chloride and the filtrate was partitionedbetween two liquid layers. The organic layer was washed with brine anddried over anhydrous magnesium sulfate. The resulting residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (7.4 g) as a yellow powder (yield:65%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.75-1.83(2H, m), 2.15-2.25(2H, m), 2.35-2.50(2H, m),2.60-2.69(2H, m), 2.78-2.87(2H, m), 3.11-3.20(2H, m), 4.12-4.28(1H, m),6.95-7.03(2H, m), 7.15-7.20(2H, m), 7.28(1H, d, J=8 Hz), 7.36(1H, s),7.49(1H, d, J=8 Hz).Example 100-3: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindole

Under ice cooling, a 1 M solution (69 ml) of a borane/tetrahydrofurancomplex in tetrahydrofuran was added dropwise into a solution of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-2,3-dioxo-6-bromoindoline (7.4g) in tetrahydrofuran (150 ml) followed by stirring at room temperatureovernight and heating under reflux for 3 hr. Into the reaction solutionwas carefully added dropwise a saturated aqueous solution of sodiumbicarbonate. Then ethyl acetate was added to the resultant mixture andthe organic layer was separated. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was then diluted with pyridine (50 ml) andstirred at room temperature for 4 hr. Next, a saturated aqueous solutionof sodium bicarbonate and ethyl acetate were added thereto and thelayers were separated. The organic layer was washed with brine and driedover anhydrous magnesium sulfate. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate system) to give the titlecompound (3.9 g) as a yellow oil (yield: 57%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.01-2.12(4H, m), 2.20-2.32(2H, m), 2.61-2.69(2H, m),2.79-2.86(2H, m), 3.13-3.21(2H, m), 4.10-4.21(1H, m), 6.48(1H, d, J=2Hz), 6.95-7.02(2H, m), 7.12-7.23(2H, m), 7.45-7.55(3H, m), 7.91(1H, t,J=6 Hz).Example 100-4: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline

Under ice cooling, a 1 M solution (20 ml) of a borane/tetrahydrofurancomplex in tetrahydrofuran was added dropwise into a solution of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-bromoindole (3.9 g) intrifluoroacetic acid (50 ml) followed by stirring for 3 hr. After addingwater thereto and concentrating under reduced pressure, the reactionmixture was basified by adding ethanol and a 5 N aqueous solution ofsodium hydroxide and then stirred for 30 min. Next, a saturated aqueoussolution of sodium bicarbonate and ethyl acetate were added thereto andthe layers were separated. The organic layer was washed with brine anddried over anhydrous magnesium sulfate. The residue was then purified bysilica gel column chromatography (toluene/acetone system) to give thetitle compound (2.0 g) as a white powder (yield: 51%).

m.p.: 99-101° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.74-1.84(4H, m), 2.10-2.19(2H, m), 2.58-2.64(2H, m),2.78-2.84(2H, m), 2.89(2H, t, J=8 Hz), 3.10-3.17(2H, m), 3.28-3.38(1H,m), 3.43(2H, t, J=8 Hz), 6.47(1H, d, J=2 Hz), 6.69(1H, dd, J=2.8 Hz),6.87(1H, d, J=8 Hz), 6.96-7.00(2H, m), 7.15-7.18(2H, m).

FAB-Mass: 404(MH+).

Example 101: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline

Triacetoxylated sodium borohydride (298 g) was added over 30 min to amixture of 6-bromoindoline (175 g), 1-(4-fluorophenethyl)-4-piperidone(194 g), acetic acid (250 ml) and dichloroethane (2.5 l) followed bystirring 2 hr. Then the reaction solution was concentrated under reducedpressure, diluted with ethyl acetate (2 l), an 8 N aqueous solution ofsodium hydroxide (1 l) and water (500 ml) and the layers were separated.The organic layer was washed successively with water (0.5 l) and brine(0.5 l), dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting residue was dissolved in hot ethylacetate (500 ml) and then cooled with ice water. The resultingcrystalline precipitates were collected by filtration to give the titlecompound (205 g) (yield: 58%).

These crude crystals were recrystallized from hexane-ethyl acetatemixtures to give the title compound as white prisms.

m.p.: 99-101° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.74-1.84(4H, m), 2.10-2.19(2H, m), 2.58-2.64(2H, m),2.78-2.84(2H, m), 2.89(2H, t, J=8 Hz), 3.10-3.17(2H, m), 3.28-3.38(1H,m), 3.43(2H, t, J=8 Hz), 6.47(1H, d, J=2 Hz), 6.69(1H, dd, J=2.8 Hz),6.87(1H, d, J=8 Hz), 6.96-7.00(2H, m), 7.15-7.18(2H, m).

FAB-Mass: 404(MH+).

Example 102: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloroindoline

1-(4-Fluorophenethyl)-4-(3-chlorophenyl)-aminopiperidine (1.4 g)synthesized in accordance with the method of Referential Example 1 ofJP-B 40-6347 was treated as in Example 101 to give the hydrochloride(380 mg) of the title compound as a white powder (yield: 25%).

m.p. (hydrochloride): 236-240° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.79-1.90(2H, m), 1.99-2.12(2H, m), 2.87(2H, t, J=8 Hz),3.00-3.13(4H, m), 3.20-3.29(2H, m), 3.36(2H, t, J=8 Hz), 3.55-3.63(2H,m), 3.70-3.80(1H, m), 6.52(1H, d, J=8 Hz), 6.57(1H, s), 6.97(1H, d, J=8Hz), 7.13-7.20(2H, m), 7.29-7.35(2H, m).

FAB-Mass: 359(MH+).

Example 103: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoroindoline

1-(Piperidin-4-yl)-6-fluoroindoline (200 mg) and 4-fluorophenethylbromide (220 mg) were treated as in Example 2 to give the hydrochloride(220 mg) of the title compound as a white powder (yield: 65%).

m.p. (hydrochloride): 214-216° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90(2H, m), 1.95-2.08(2H, m), 2.85(2H, t, J=8 Hz),2.99-3.10(4H, m),3.20-3.29(2H, m),3.38(2H, t, J=8 Hz), 3.67-3.75(3H, m),6.26(1H, t, J=8 Hz), 6.39(1H, d, J=8 Hz), 6.95(1H, t, J=8 Hz),7.14-7.19(2H, m), 7.30-7.34(2H, m).

FAB-Mass: 343(MH+).

Example 104: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyindoline

A solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline(1.6 g) in conc. hydrogen bromide (40 ml) was heated at 100° C. for 2hr. Next, it was basified with a conc. aqueous solution of sodiumhydroxide and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (methylene chloride/ethanol system) followed byconversion into a hydrochloride in a conventional manner. Thus thehydrochloride (1.2 g) of the title compound was obtained as brown prisms(yield: 68%).

m.p. (hydrochloride): 232° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-2.00(4H, m), 2.73(2H, t, J=8 Hz), 2.97-3.12(4H, m),3.21-3.33(4H, m), 3.59-3.69(3H, m), 5.93(1H, s), 5.97(1H, d, J=8 Hz),6.75(1H, d, J=8 Hz), 7.12-7.21(2H, m), 7.30-7.38(2H, m), 8.89(1H, s).

FAB-Mass: 341(MH+).

Example 105: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-4-methoxyindoline

A mixture of 4-methoxyindoline (0.25 g),1-(4-fluorophenethyl)-4-piperidone, platinum oxide (50 mg), -acetic acid(1.0 ml) and ethanol (20 ml) was catalytically reduced under hydrogenatmosphere at ordinary temperature under atmospheric pressure. Afterstirring the reaction mixture overnight, the catalyst was filtered offand the filtrate was concentrated under reduced pressure. Then it wasdiluted with a saturated aqueous solution of sodium bicarbonate andethyl acetate and the layers were separated. The organic layer waswashed with brine and dried over anhydrous magnesium sulfate. Theresulting residue was purified by silica gel column chromatography(hexane/ethyl acetate system) followed by conversion into ahydrochloride in a conventional manner. Thus the hydrochloride (92 mg)of the title compound was obtained as a white powder (yield: 27%).

m.p. (hydrochloride): 195-198° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-2.04(4H,m), 2.79(2H, t, J=8 Hz), 3.00-3.13(4H, m),3.21-3.36(4H, m), 3.59-3.71(3H, m), 3.72(3H, s), 6.22(1H, d, J=8 Hz),6.27(1H, d, J=8 Hz), 6.98(1H, t, J=8 Hz), 7.15-7.20(2H, m),7.31-7.35(2H, m).

FAB-Mass: 355(MH+).

Example 106-1: Synthesis of1-(1-benzylpiperidin-4-yl)-6-methoxyindoline-2,3-dione

1-Benzyl-4-(3-methoxyphenyl)aminopiperidine (1.88 g) synthesized inaccordance with the method of Referential Example 1 of JP-B 40-6347 wasdissolved in ether (38 ml). Into the resultant solution was addeddropwise oxalyl chlori de (1.62 g) over 30 min at room temperaturefollowed by heating under reflux for 3.5 hr. After cooling to roomtemperature, the reaction solution was concentrated under reducedpressure. Into a suspension of aluminum chloride (5.9 g) in methylenechloride (20 ml) was added dropwise a solution of the resulting residuein methylene chloride (100 ml) at 0° C. over 30 min. After thecompletion of the addition, the resultant mixture was stirred at roomtemperature for additional 1.5 hr. After the completion of the reaction,the reaction solution was poured into ice and neutralized by adding anaqueous solution of sodium bicarbonate thereto. The resultingprecipitate was filtered off and the filtrate was extracted withmethylene chloride. After removing the solvent, the resulting residuewas purified by silica gel column chromatography (hexane/ethyl acetatesystem) to give 1-(1-benzylpiperidin-4-yl)-6-methoxyindoline-2,3-dione(1.63 g) (yield: 73%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.69-1.76(2H, m), 2.12(2H, br-t), 2.42(2H, dq, J=12.0, 4.0 Hz),3.03(2H, br-d), 3.55(2H, s), 3.93(3H, s), 4.08-4.18(1H, m), 6.54(1H, dd,J=8.4, 1.6 Hz), 6.66(1H, d, J=1.6 Hz), 7.24-7.36(5H, m), 7.59(1H, d,J=8.4 Hz).Example 106-2: Synthesis of 1-(1-benzylpiperidin-4-yl)-6-methoxyindole

A 2 M solution (0.47 ml) of a diborane/dimethyl sulfide complex intetrahydrofuran was added to a solution of1-(1-benzylpiperidin-4-yl)-6-methoxyindoline-2,3-dione (110 mg) intetrahydrofuran (2 ml) followed by stirring for 1 hr and then heatingunder reflux for 4.5 hr. After the completion of the reaction, anaqueous solution of sodium bicarbonate was added to the reactionsolution, which was then extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate andthe solvent was removed. Theresidue was dissolved in pyridine and stirred for 4.5 hr. Afterevaporating off pyridine, ethyl acetate and an aqueous solution ofsodium bicarbonate were added thereto. The ethyl acetate layer wasseparated and dried over magnesium sulfate. After distilling off thesolvent, the resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give1-(1-benzylpiperidin-4-yl)-6-methoxyindole (28 mg) (yield: 28%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.02-2.12(4H, m), 2.17-2.27(2H, m), 3.07(2H, br-d), 3.60(2H, s),3.87(3H, s), 4.09-4.18(1H, m), 6.44(1H, d, J=3.2 Hz), 6.78(1H, dd,J=8.8, 2.0 Hz), 6.82(1H, br-d), 7.13(1H, d, J=3.2 Hz), 7.25-7.37(5H, m),7.49(1H, d, J=8.8 Hz).Example 106-3: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindole

1-Chloroethyl chloroformate (32 mg) was added to a solution of1-(1-benzylpiperidin-4-yl)-6-methoxyindole (24 mg) in toluene (2 ml)followed by heating under reflux for 3 hr. The reaction solution wasconcentrated under reduced pressure and the resulting residue wasdissolved in methanol followed by heating under reflux for 9 hr. Afterthe completion of the reaction, methanol was evaporated and the residuewas dissolved in dimethylformamide (1 ml). Next, 2-(4-fluorophenyl)ethylbromide (19 mg) was added thereto and the resultant mixture was stirredat 60° C. for 11 hr. After the completion of the reaction, brine wasadded to the mixture. Then it was extracted with ethyl acetate and driedover magnesium sulfate. After removing the solvent, the resultingresidue was purified by silica gel column chromatography(toluene/acetone system) to give the title compound (7 mg) (yield: 27%).

m.p.: 230° C. (decomp.).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.06-2.14(4H, m), 2.25-2.33(2H, m), 2.67(2H, dd, J=9.2, 10.8 Hz),2.83(2H, dd, J=10.8, 9.2 Hz), 3.20(2H, br-d, J=11.6 Hz), 3.88(3H, s),4.12-4.21(1H, m), 6.45(1H, d, J=3.2 Hz), 6.79(1H, dd, J=8.4, 2.0 Hz),6.83(1H, d, J=2.0 Hz), 6.99(2H, t, J=12.4 Hz), 7.14(1H, d, J=3.2 Hz),7.18(2H, dd, J=8.4, 5.6 Hz), 7.50(1H, d, J=8.4 Hz).

MS; [M+H]+: m/z=353.

Example 106-4: Synthesis of1-[1-(4-flourophenethyl)piperidin-4-yl]-6-methoxyindoline

A 1 M solution (0.18 ml) of a borane/tetrahydrofuran complex was addeddropwise at 0° C. into a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindole (24 mg) intrifluoroacetic acid (1 ml) over 2 min followed by stirring at 0° C. for30 min. Af ter the completion of the reaction, water (0.1 ml) was addedthereto and the resulting reaction solution was concentrated underreduced pressure. The resulting residue was dissolved in a 2 N aqueoussolution of sodium hydroxide and stirred at room temperature for 10 min.The mixture was extracted with methylene chloride. The organic layer wasseparated and dried over magnesium sulfate. After concentrating thesolvent under reduced pressure, the resulting residue was purified bypreparative TLC to give1-[1-(4-fluorophenethyl)piperidin-4-yl)]-6-methoxyindoline (10 mg)(yield: 35%).

m.p.: 242° C. (decomp.).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.75-1.90(4H, m), 2.10-2.22(2H, m), 2.58-2.70(2H, m), 2.80(2H,dd, J=11.6, 7.2 Hz), 2.88(2H, t, J=8.8 Hz), 3.14(2H, br-d, J=10.8 Hz),3.31-3.82(1H, m), 3.41(2H, t, J=8.4 Hz), 3.77(3H, s), 6.00(1H, d, J=2.0Hz), 6.13(1H, dd, J=8.0, 2.0 Hz), 6.93(1H, 2H, t, J=8.8 Hz), 6.97(2H, t,J=8.8 Hz), 7.16(2H, dd, J=8.4, 5.6 Hz).

MS; [M+H]+: m/z=355.

Example 107: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]7-methoxyindoline

1-(4-Fluorophenethyl)-4-(2-methoxyphenyl)-aminopiperidine (3.9 g)synthesized in accordance with the method of Referential Example 1 ofJP-B 40-6347 was treated as in Example 106 to give the hydrochloride(530 mg) of the title compound as a white powder (yield: 11%).

m.p. (hydrochloride): 204-206° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.72-1.80(2H, m), 1.90-2.40(2H, m), 2.86(2H, t, J=8 Hz),2.95-3.08(4H, m), 3.21-3.34(4H, m), 3.55-3.63(2H, m), 3.73(3H, s),4.24-4.34(1H, m), 6.60-6.64(1H, m), 6.69-6.74(2H, m), 7.14-7.19(2H, m),7.28-7.32(2H, m).

FAB-Mass: 355(MH+).

Example 108: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6,7-dimethoxyindoline

1-(4-Fluorophenethyl)-4-(2,3-dimethoxyphenyl)aminopiperidine (8.1 g)synthesized in accordance with the method of Referential Example 1 ofJP-B 40-6347 was treated as in Example 106 to give the oxalate (34 mg)of the title compound as a white powder (yield: 1.7%).

m.p. (oxalate): 179-181° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.72-1.86(4H, m), 2.79(2H, t, J=8 Hz), 2.86-2.97(2H, m),3.04-3.18(2H, m), 3.29(2H, t, J=8 Hz), 3.40-3.58(4H, m), 3.64 (3H, S),3.69 (3H, s), 4.05-4.17 (1H, m), 6.25 (1H, d, J=8 Hz) 6.69(1H, d, J=8Hz), 7.13-7.18(2H, m), 7.28-7.32(2H, m).

FAB-Mass: 385(MH+)

Example 109: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-nitroindoline

1-(Piperidin-4-yl)-6-nitroindoline (3.5 g) and 4-fluorophenethyl bromide(4.1 g) were treated as in Example 2 to give the title compound (5.1 g)as apaleyellowpowder (yield: 81%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.71-2.89(4H, m), 2.09-2.20(2H, m), 2.55-2.66(2H, m),2.76-2.83(2H, m), 3.03(2H, t, J=8 Hz), 3.10-3.19(2H, m), 3.39-3.49(1H,m), 3.56(2H, t, J=8 Hz), 6.95-7.00(2H, m), 7.09(1H, d, J=8 Hz), 7.10(1H,s), 7.12-7.21(2H, m), 7.50(1H, d, J=8 Hz)Example 110: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6aminoindoline

A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-nitroindoline(5.1 g), powdery iron (5.0 g), ammonium chloride (10 g), water (20 ml)and ethanol (100 ml) was stirred at 60° C. for 4 hr. Next, the reactionsolution was filtered and the filtrate was concentrated under reducedpressure. Then a 5 N aqueous solution of sodium hydroxide and ethylacetate were added thereto and the layers were separated. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Then the resulting residue waspurified by silica gel column chromatography (methylene chloride/ethanolsystem) to give the title compound (3.4 g) as a brown powder (yield:73%).

m.p. 104-106° C.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.69-1.88(4H, m), 2.05-2.13(2H, m), 2.53-2.60(2H, m),2.71-2.81(2H, m), 2.83(2H, t, J=8 Hz), 3.09-3.13(2H, m), 3.29-3.35(1H,m), 3.36(2H, t, J=8 Hz), 3.50(2H, br-s), 5.82(1H, s), 5.98(1H, d, J-=8Hz), 6.81(1H, d, J=8 Hz), 6.91-7.00(2H, m), 7.12-7.20(2H, m).

FAB-Mass: 340(MH+).

Example 111: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4yl]-6-methylaminoindoline

Ethyl chlorocarbonate (100 mg) was added dropwise at room temperatureinto a solution of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-aminoindoline (0.3 g) andtriethylamine (100 mg) in methylene chloride (5 ml). Then the resultantmixture was stirred for 30 min and concentrated under reduced pressure.The resulting residue was partitioned between water and ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue was addedto a suspension of lithium aluminum hydride (67 mg) in tetrahydrofuran(5 ml) and heated under reflux for 1 hr. Under ice cooling, water (0.14ml), a 5 N aqueous solution (0.42 ml) of sodium hydroxide and furtherwater (0.14 ml) were carefully added dropwise into the reaction solutionfollowed by vigorous stirring. The resulting precipitate was filteredoff and the filtrate was concentrated under reduced pressure. Next, theobtained residue was purified by NH-silica gel column chromatography(hexane/ethyl acetate system) followed by conversion into ahydrochloride in a conventional manner. Thus the hydrochloride (220 mg)of the title compound was obtained as a brown hygroscopic amorphoussolid (yield: 64%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90(2H, m), 1.99-2.13(2H, m), 2.82(3H, s), 2.90(2H, t, J=8Hz), 3.00-3.12(4H, m), 3.20-3.33(2H, m), 3.41(2H, t, J=8 Hz),3.59-3.69(2H, m), 3.80-3.90(1H, m), 6.56-6.62(2H, m), 7.09(1H, d, J=8Hz), 7.12-7.20(2H, m), 7.29-7.35(2H, m).

FAB-Mass: 354(MH+).

Example 112: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ethylaminoindoline

A mixture of 1-1-(4-fluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.3g), pyridine (5 ml) and acetic anhydride (3 ml) was stirred at roomtemperature for 30 min. After concentrating the resultant mixture underreduced pressure, water and ethyl acetate were added thereto and thelayers were separated. The organic layer was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was added to a suspension of lithium aluminumhydride (127 mg) in tetrahydrofuran (5 ml) and heated under reflux for 1hr. Under ice cooling, water (0.14 ml), a 5 N aqueous solution (0.42 ml)of sodium hydroxide and further water (0.14 ml) were carefully addeddropwise into the reaction solution followed by vigorous stirring. Theresulting precipitate was filtered off and the filtrate was concentratedunder reduced pressure. Next, the resulting residue was purified byNH-silica gel column chromatography (hexane/ethyl acetate system)followed by conversion into a hydrochloride in a conventional manner.Thus the hydrochloride (210 mg) of the title compound was obtained as apale brown hygroscopic amorphous solid (yield: 59%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.20(3H, t, J=7 Hz), 1.82-1.91(2H, m), 2.01-2.10(2H, m), 2.89(2H,t, J=8 Hz), 3.00-3.09(4H, m), 3.21-3.32(4H, m), 3.39(2H, t, J=8 Hz)3.60-3.72(3H, m ), 6.55-6.62(2H, m ), 7.09(1H, d, J=8 Hz), 7.10-7.21(2H,m), 7.28-7.33(2H, m).

FAB-Mass: 368(MH+).

Example 113: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-isopropylaminoindioline

1-[l-(4-Fluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.3 g), acetone(0.075 g), acetic acid (0.23 g) and triacetoxylated sodium borohydride(0.36 g) were treated as in Example 101 to give the hydrochloride (240mg) of the title compound as a pale brown, hygroscopic and amorphoussolid (yield: 65%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.23(6H, d, J=7 Hz),1.80-1.91(2H, m), 2.02-2.20(2H, m), 2.91(2H,t, J=8 Hz), 3.00-3.13(4H, m), 3.20-3.29(2H, m), 3.40(2H, t, J=8 Hz),3.60-3.71(4H, m), 6.61-6.69(2H, m), 7.09(1H, d, J=8 Hz), 7.11-7.20(2H,m), 7.31-7.39(2H, m).

FAB-Mass: 382(MH+).

Example 114: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-dimethylaminoindoline

6-Dimethylaminoindoline (0.6 g), 1-(4-fluorophenethyl-4-piperidone (0.98g), acetic acid (1.1 g) and triacetoxylated sodium borohydride (1.2 g)were treated as in Example 101 to give the hydrochloride (0.77 g) of thetitle compound as a white powder (yield: 52%).

m.p. (hydrochloride): 205-208° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-2.03(4H, m), 2.71(2H, t, J=8 Hz),2.80(6H, s) 2.99-3.13(4H,m), 3.20-3.31(4H, m), 3.53-3.67(2H, m), 3.70-3.80(1H, m), 5.89-5.99(2H,m), 6.80(1H, d, J=8 Hz), 7.11-7.19(2H, m), 7.29-7.36(2H, m).

FAB-Mass: 367(MH+).

Example 115: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-acetamidoindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminoindoline (1.0 g) andacetic anhydride (1 ml) were treated as in Example 133 to give the titlecompound (450 mg) as a pale yellow powder (yield: 41%).

m.p.: 148-150° C.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.80-1.91(4H, m), 2.15(3H, s), 2.20-2.35(2H, m), 2.62-2.75 (2H,m), 2.81-2.97 (2H, m), 2.90 (2H, t, J=8 Hz), 3.13-3.29 (2H, m),3.39-3.48 (1H, m), 3.42 (2H, t, J=8 Hz), 6.44 (1H, d, J=8 Hz),6.93-7.01(4H, m), 7.16-7.20(3H, m).

FAB-Mass: 382(MH+)

Example 116: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-methanesulfonylaminoindoline

Methanesulfonyl chloride (0.4 g) was added dropwise at 0° C. into amixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.3g), 4-dimethylaminopyridine (0.1 g) and pyridine (10 ml) followed bystirring for 2 hr. Then water and ethyl acetate were added to thereaction solution and the layers were separated. The organic layer waswashed with water and brine and dried over anhydrous magnesium sulfate.The residue was purified by NH-silica gel column chromatography(hexane/ethyl acetate system) followed by conversion into ahydrochloride in a conventional manner. Thus the hydrochloride (160 mg)of the title compound was obtained as a pale yellow hygroscopicamorphous solid (yield: 40%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80-2.03 (4H, m), 2.85 (2H, t, J=8 Hz), 2.89 (3H, s),2.99-3.17(4H, m), 3.20-3.43(5H, m), 3.58-3.69(2H, m), 6.37-6.40 (2H, m),6.94 (1H, d, J=8 Hz), 7.15-7.20 (2H, m), 7.30-7.34 (2H, m), 9.33(1H, s).

FAB-Mass: 418(MH+).

Example 117: Synthesis of of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-ethanesulfonylaminoindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.4 g) andethanesulfonyl chloride (0.61 g) were treated as in Example 116 to givethe hydrochloride (160 mg) of the title compound as a brown hygroscopicamorphous solid (yield: 29%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.16(3H, t, J=7 Hz), 1.81-1.89(2H, m), 1.94-2.05(2H, m), 2.82(2H,t, J=8 Hz), 2.98(2H, q, J=7 Hz), 2.99-3.16(4H, m), 3.20-3.29(2H, m),3.31(2H, t, J=8 Hz), 3.35-3.44(1H, m), 3.55-3.68(2H, m), 6.37-6.39(2H,m), 6.93(1H, d, J=8 Hz), 7.13-7.19(2H, m), 7.29-7.33(2H, m), 9.42(1H,s).

FAB-Mass: 432(MH+).

Example 118: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-propanesulfonylaminoindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.4 g) andpropanesulfonyl chloride (0.67 g) were treated as in Example 116 to givethe hydrochloride (210 mg) of the title compound as a white powder(yield: 37%).

m.p. (hydrochloride): 166-169° C.

¹H-NMR (400 MHz, DMSO-d₆)

δ(ppm) 0.91(3H, t, J=7 Hz), 1.65(2H, sextet, J=7 Hz), 1.82-2.04(4H, m),2.84(2H, t, J=8 Hz), 2.94(2H, q, J=7 Hz), 3.00-3.16(4H, m),3.22-3.43(5H, m), 3.59-3.68(2H, m), 6.38-6.40(2H, m), 6.91(1H, d, J=8Hz), 7.11-7.20(2H, m), 7.30-7.38(2H, m), 9.41(1H, s).

FAB-Mass: 446(MH+).

Example119: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(4-fluorobenzenesulfonylamino)indoline

6-(4-Fluorobenzenesulfonylamino)indoline (0.23 g),1-(4-fluorophenethyl)-4-piperidone (0.33 g), acetic acid (0.36 g) andtriacetoxylated sodium borohydride (0.42 g) were treated as in Example101 to give the hydrochloride (0.29 g) of the title compound as a whitepowder (yield: 68%).

m.p. (hydrochloride): 140-143° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.69-1.73(2H, m), 1.83-1.99(2H, m), 2.75(2H, t, J=8 Hz),3.01-3.19(4H, m), 3.20-3.31(4H, m), 3.51-3.63(3H, m) 6.12(1H, d, J=8Hz), 6.28(1H, s), 6.81(1H, d, J=8 Hz), 7.13-7.21(2H, m), 7.30-7.41(4H,m), 7.74-7.79(2H, m).

FAB-Mass: 498(MH+)

Example 120: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(N-methylmethanesulfonylamino)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-methylaminoindoline (150 mg)and methanesulfonyl chloride (54 mg) were treated as in Example 116 togive the hydrochloride (100 mg) of the title compound as white prisms(yield: 55%).

m.p. (hydrochloride): 136-139° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.82-1.89(2H, m), 1.98-2.10(2H, m), 2.83-2.90(2H, m), 2.90(3H,s), 3.01-3.14(4H, m), 3.17(3H, s), 3.20-3.28(2H, m), 3.32-3.40(2H, m),3.58-3.76(3H, m), 6.54-6.59(2H, m), 7.01(1H, d, J=8 Hz), 7.14-7.19(2H,m), 7.30-7.34(2H, m).

FAB-Mass: 432(MH+).

Example 121: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-hydroxyethoxyindoline

60% sodium hydride (0.11 g) was added to a solution of1-[1-(4-fluorophenethyl)pipe ridin-4-yl]-6-hydroxyindoline (0.8 g) indimethylf ormamide (30 ml) and the resultant mixture was stirred at 50°C. After 10 min, (t-butyl)dimethyl-siloxyethyl bromide (0.67 g) wasadded to the reaction solution followed by stirring for additional 2 hr.Then the mixture was concentrated under reduced pressure, diluted with a2 N aqueous solution of sodium hydroxide and ethyl acetate and thelayers were separated. The organic layer was washed with brine, driedover anhydrous magnesium sulf ate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(methylene chloride/ethanol system). To the residue were added a 1 Msolution (2.4 ml) of tetrabutylammonium fluoride in tetrahydrofuran andtetrahydrofuran (20 ml) and the resultant mixture was stirred at roomtemperature for 3 hr. Next, the mixture was diluted with a 2 N aqueoussolution of sodium hydroxide and ethyl acetate and the layers wereseparated. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (methylenechloride/ethanol system) followed by conversion into a hydrochloride ina conventional manner to give the hydrochloride (300 mg) of the titlecompound as a white powder (yield: 25%).

m.p. (hydrochloride): 235-238° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.84-1.99(2H, m), 2.79(2H, t, J=8 Hz), 2.97-3.14(4H, m),3.22-3.34(4H, m), 3.60-3.77(5H, m), 3.88(2H, t, J=5 Hz), 4.79(1H, br-s),6.09(1H, d, J=8 Hz), 6.12(1H, s), 6.88(1H, d, J=8 Hz), 7.12-7.20(2H, m),7.30-7.38(2H, m).

FAB-Mass: 385(MH+).

Example 122: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6methanesulfonyloxyindoline

A solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline(1.0 g) in conc. hydrogen bromide (20 ml) was heated at 100° C. for 2hr. Next, the mixture was basified with a conc. aqueous solution ofsodium hydroxide and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved inpyridine (10 ml) and methanesulfonyl chloride (0.46 g) was addeddropwise thereinto under ice cooling. After stirring overnight, theresultant mixture was concentrated under reduced pressure, diluted witha 2 N aqueous solution of sodium hydroxide and ethyl acetate and thelayers were separated. The organic layer was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. Then the residue was purified by NH-silica gel columnchromatography (ethyl acetate/hexane system) followed by conversion intoa hydrochloride in a conventional manner to give the hydrochloride (300mg) of the title compound as a pale brown powder (yield: 15%).

m.p. (hydrochloride): 220-223° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-1.92(2H, m), 1.94-2.06(2H, m), 2.90(2H, t, J=8 Hz),3.00-3.14(4H, m), 3.21-3.28(2H, m), 3.30(3H, s), 3.34-3.44(2H, m),3.59-3.66(2H, m), 3.68-3.78(1H, m), 6.46-6.48(2H, m), 7.04(1H, d, J=8Hz), 7.15-7.19(2H, m), 7.30-7.34(2H, m).

FAB-Mass: 419(MH+).

Example 123: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-7-hydroxyethoxyindoline

A solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-methoxyindoline(0.3 g) in conc. hydrogen bromide (6 ml) was heated at 100° C. for 2 hr.Then the solution was basified with a conc. aqueous solution of sodiumhydroxide and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The resulting residue was dissolved indimethylformamide (10 ml) and 60% sodium hydride (32 mg) was addedthereto followed by stirring at 50° C. After 30 min,(t-butyl)dimethylsiloxyethyl bromide (0.19 g) was added to the reactionsolution and the resultant mixture was stirred for additional 30 min.After concentrating underreduced pressure, it was diluted with a 2 Naqueous solution of sodium hydroxide and ethyl acetate and the layerswere separated. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/methanol system). To the residue were added a 1 M solution (0.45ml) of tetrabutylammonium fluoride in tetrahydrofuran andtetrahydrofuran (10 ml) and the resultant mixture was stirred at roomtemperature overnight. Then it was diluted with a 2 Naqueous solution ofsodium hydroxide and ethyl acetate and the layers were separated. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/methanolsystem) followed by conversion into a hydrochloride in a conventionalmanner to give the hydrochloride (80 mg) of the title compound as awhite, hygroscopic and amorphous solid (yield: 25%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.79-1.86(2H, m), 1.95-2.07(2H, m), 2.91(2H, t, J=8 Hz),2.95-3.07(4H, m), 3.20-3.27(2H, m), 3.30-3.41(2H, m), 3.56-3.63(2H, m),3.74(2H, t, J=5 Hz), 3.96(2H, t, J=5 Hz), 4.38-4.47(1H, m),6.69-6.80(3H, m), 7.11-7.21(2H, m), 7.29-7.35(2H, m).

FAB-Mass: 385(MH+).

Example 124: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanoindoline

Trifluoromethanesulfonic anhydride (0.72 ml) was added dropwise at −78°C. into a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindoline(1.5 g) and triethylamine (1.2 ml) in methylene chloride (1 l) and theresultant mixture was warmed to room temperature. Next, a saturatedaqueous solution of sodium bicarbonate and chloroform were added theretoand the layers were separated. The organic layer was dried overanhydrous magnesium sulfate and the residue was purified by NH-silicagel column chromatography (hexane/ethyl acetate system) to give thetitle compound (1.0 g) as a white powder (yield: 67%).

A portion of these crystals were converted into a hydrochloride in aconventional manner to give the hydrochloride of the title compound aswhite powdery crystals.

m.p. (hydrochloride): 230° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.82-1.91(2H, m), 1.95-2.09(2H, m), 2.98(2H, t, J=8 Hz),3.00-3.13 (4H, m),3.21-3.30 (2H, m),3.41 (2H, t, J=8 Hz), 3.59-3.68(2H,m), 3.74-3.83(1H, m), 6.90(1H, s), 6.96(1H, d, J=8 Hz), 7.11-7.20(3H,m), 7.30-7.39(2H, m), 10.51(1H, br-s).

FAB-Mass: 350(MH+).

Example 125: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-carbamoylindoline

A solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanoindoline(1.0 g) in conc. sulfuric acid (1 l) was heated at 50° C. for 2 hr.After diluting with ice water, the reaction solution was basified with aconc. aqueous solution of sodium hydroxide. Then ethyl acetate was addedthereto and the layers were separated. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the title compound (0.81 g) as a white powder(yield: 77%).

A portion of these crystals were converted into a hydrochloride in aconventional manner to give the hydrochloride of the title compound as awhite powder.

m.p. (hydrochloride): 160-162° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.87-1.95(2H, m), 1.99-2.13(2H, m), 2.94(2H, t, J=8 Hz),3.04-3.17(4H, m), 3.24-3.31(2H, m), 3.38(2H, t, J=8 Hz) 3.60-3.68(2H,m), 3.73-3.83(1H, m), 7.01(1H, s), 7.07(1H, d, J=8 Hz),7.12(1H, d, J=8Hz),7.16-7.21(3H, m),7.32-7.36(2H, m), 7.79(1H, br-s).

FAB-Mass: 368(MH+).

Example 126: Synthesis of1-[1-(4-fluorophenethyl)-piperdine-4-yl]-6-(1-pyrrolylcarhonyl)indoline

A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylindoline(0.3 g), 1,4-dichloro-1,4-dimethoxybutane (0.7 g), Amberlyst A-21 (0.5g) and acetonitrile (10 ml) was heated at 60° C. for 10 hr. Afterfiltering, the reaction solution was basif ied with a saturated aqueoussolution of sodium bicarbonate and then ethyl acetate was added theretoand the layers were separated. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate system) followed by conversion into an oxalate ina conventional manner to give the oxalate (0.13 g) of the title compoundas a pale yellow powder (yield: 31%).

m.p. (oxalate): 169-171° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-1.94(4H, m), 2.90-2.97(4H, m), 3.02 (2H, t, J=8 Hz),3.08-3.19(2H, m), 3.41-3.55(4H, m), 3.72-3.83(1H, m) 6.37(2H, s),6.80(1H, s), 6.89(1H, d, J=8 Hz), 7.14-7.21(3H, m), 7.28-7.34(4H, m).

FAB-Mass: 418(MH+).

Example 127: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-acetylindoline

A 2.5 M solution (1.5 ml) of n-butyllithium in hexane was added dropwiseat −78° C. into a solution (30 ml) of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (1.0 g) intetrahydrofuran over 5 min. After 10 min, dimethylacetamide (0.34 ml)was added thereto and the resultant mixture was warmed to roomtemperature. Next, a saturated aqueous solution of ammonium chloride andethyl acetate were added thereto to and the layers were separated. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by NH-silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (250 mg) as a yellow powder (yield:27%).

m.p. 90-92° C.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.71-1.86(4H, m), 2.12-2.22(2H, m), 2.56(3H, s), 2.57-2.64(2H,m), 2.77-2.84(2H, m), 2.99(2H, t, J=8 Hz), 3.07-3.16(2H, m),3.42-3.56(1H, m), 3.46(2H, t, J=8 Hz), 6.94-6.99(3H, m), 7.08(1H, d, J=8Hz), 7.14-7.23(3H, m).

FAB-Mass: 367(MH+).

Example 128: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-methanesulfonylindoline

A 2.5 M solution (0.6 ml) of n-butyllithium in hexane was added dropwiseat −78° C. into a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (470 mg) intetrahydrofuran (20 ml) over 10 min. After 10 min, a saturated solutionof sulfur dioxide in tetrahydrofuran (50 ml) was added thereto and theresultant mixture was warmed to room temperature. After concentratingthe reaction solution under reduced pressure, dimethylformamide (10 ml)and methyl iodide (100 mg) were added to the residue and the resultantmixture was stirred at room temperature overnight. Then the reactionsolution was concentrated under reduced pressure, a saturated aqueoussolution of sodium bicarbonate and ethyl acetate were added thereto andthe layers were separated. The organic layer was washed with brine anddried over anhydrous magnesium sulfate. The residue was purified byNH-silica gel column chromatography (hexane/ethyl acetate system)followed by conversion into a hydrochloride in a conventional manner togive the hydrochloride (20 mg) of the title compound as brown prisms(yield: 3.8%).

m.p. (hydrochloride): 228° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-2.09(4H, m), 2.98-3.18(6H, m), 3.10(3H, s), 3.20-3.31(2H,m), 3.44(2H, t, J=8 Hz), 3.59-3.68(2H, m), 3.80-3.93 (1H, m), 6.91(1H,s), 7.06(1H, d, J=8 Hz), 7.14-7.23 (3H, m), 7.30-7.35(2H, m)

FAB-Mass: 403(MH+).

Example 129: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-thiocarbamoylmethylindoline

A mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindoline (720mg), phosphorus pentasulfide (250 mg) and pyridine (20 ml) was heatedunder reflux for 1 hr. Then the mixture was diluted with a 5 N aqueoussolution of sodium hydroxide and ethyl acetate. The organic layer waswashed with brine and dried over anhydrous magnesium sulfate. Theresidue was purified by NH-silica gel column chromatography(hexane/ethyl acetate system) followed by conversion into ahydrochloride in a conventional manner to give the hydrochloride (170mg) of the title compound as a white hygroscopic amorphous solid (yield:21%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.86-1.94(2H, m), 2.02-2.15(2H, m), 2.86(2H, t, J=8 Hz),3.03-3.16(4H, m), 3.22-3.30(2H, m), 3.33(2H, t, J=8 Hz), 3.60-3.74(3H,m), 3.70(2H, s), 6.57(1H, d, J=8 Hz), 6.61(1H, s), 6.95(1H, d, J=8 Hz),7.16-7.21(2H, m), 7.32-7.36(2H, m), 9.26(1H, br-s), 9.42(1H, br-s),10.60(1H, br-s).

FAB-Mass: 398(MH+).

Example 130: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-formylindoline

A 2.5 M solution (50 ml) of n-butyllithium in hexane was added dropwiseat −78° C. into a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (40 g) intetrahydrofuran (1 l) over 10 min. After 10 min, dimethylformamide (11.6ml) was added thereto and the resultant mixture was warmed to roomtemperature. Next, a saturated aqueous solution of ammonium chloride(200 ml) and ethyl acetate (500 ml) were added thereto and the layerswere separated. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive the crude title compound (37.5 g). A portion of this crude productwas purified by silica gel column chromatography (ethyl acetate/ethanolsystem) to give the title compound as a yellow powder.

m.p.: 109-111° C.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.78-1.80(4H, m), 2.10-2.29(2H, m), 2.59-2.68(2H, m),2.79-2.90(2H, m), 3.03(2H, t, J=8 Hz), 3.10-3.19(2H, m), 3.42-3.53 (1H,m), 3.50 (2H, t, J=8 Hz), 6.82 (1H, s), 6.91-7.00 (2H, m), 7.09(1H, d,J=8 Hz), 7.13-7.19(3H, m), 9.85(1H, s).

FAB-Mass: 353(MH+).

Example 131: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-hydroxyiminomethylindoline

A suspension of crude1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (35 g),hydroxylammonium chloride (10.4 g) and anhydrous sodium acetate (12.3 g)in ethanol (400 ml) was stirred at room temperature for a day. Then thereaction solution was concentrated under reduced pressure, diluted withethyl acetate (500 ml), an 8 N aqueous solution (30 ml) of sodiumhydroxide and water (100 ml) and the layers were separated. The organiclayer was washed with brine and dried over magnesium sulfate. Afterremoving the solvent, the residue was dissolved in a hot toluene (100ml)-isopropyl ether (100 ml) mixtures and allowed to cool at roomtemperature. The resulting crystals were collected by filtration anddried at 50° C. to give the title compound (31 g) as a pale yellowpowder (yield: 85%).

m.p.: 152-154° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.78-1.85(4H, m), 2.08-2.20(2H, m), 2.56-2.64(2H, m),2.78-2.84(2H, m), 2.92(2H, t, J=8 Hz), 3.10-3.19(2H, m), 3.40-3.50(1H,m), 3.46(2H, t, J=8 Hz), 6.69(1H, s), 6.70(1H, d, J=8 Hz), 6.92-7.00(2H,m), 7.03(1H, d, J=8 Hz), 7.15-7.20(2H, m), 8.06(1H, s).

FAB-Mass: 368(MH+).

Example 132: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline

Under ice cooling and stirring,1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindoline (31g) was added in portions to a suspension of lithium aluminum hydride(8.0 g) in tetrahydrofuran (500 ml) and then the resultant mixture washeated under reflux for 3 hr. Under cooling with ice water, water (8ml), a 5 N aqueous solution (24 ml) of sodium hydroxide and furtherwater (8 ml) were carefully added dropwise to the reaction solutionfollowed by vigorous stirring. The resulting precipitate was filteredoff and the filtrate was concentrated under reduced pressure to give thecrude title compound (about 30 g). A portion of this crude product waspurified by NH-silica gel column chromatography (ethyl acetate) andrecrystallized from ethyl acetate-isopropyl ether mixtures to give thetitle compound as a pale yellow powder.

m.p.: 83-85° C.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.52-2.02 (6H, m), 2.10-2.20 (2H, m), 2.56-2.63 (2H, m),2.78-2.83(2H, m), 2.91(2H, t, J=8 Hz), 3.10-3.18(2H, m), 3.37-3.50 (1H,m), 3.41 (2H, t, J=8 Hz), 3.69 (2H, s), 6.39 (1H, s) 6.51(1H, d, J=8Hz), 6.93-7.01(3H, m), 7.12-7.20(2H, m).

FAB-Mass: 354(MH+).

Example 133: Synthesis of1-[1-(4-fluorophenethylpiperdin-4-yl]-6-acetamidomethylindoline

Under ice cooling, acetyl chloride (6.6 ml) was added dropwise into asolution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (30 g)obtained above and triethylamine (9.4 g) in acetonitrile (500 ml) andthe resultant mixture was stirred at room temperature for 1 hr. Afteradding a 5 N aqueous solution (40 ml) of sodium hydroxide and water (500ml) to the reaction solution, the resulting crystalline precipitateswere collected by filtration, washed successively with water and ethylacetate and then dried at 50° C. overnight to give the crude titlecompound (22.8 g). This crude product was recrystallized successivelyfrom ethyl acetate and ethanol to give the title compound (17.9 g) aswhite needles (yield: 54%).

m.p.: 160 162° C.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.78-1.86(4H, m), 2.01(3H, s), 2.12-2.28(2H, m) 2.58-2.72(2H, m),2.76-2.89(2H, m), 2.93(2H, t, J=8 Hz), 3.08-3.26(2H,m), 3.35-3.46(1H,m), 3.42(2H, t, J=8 Hz) 4.33(2H, d, J=6 Hz), 5.69(1H, br-s), 6.34(1H,s), 6.51(1H, d, J=8 Hz), 6.95-7.02(3H, m), 7.14-7.20(2H, m).

FAB-Mass: 396(MH+).

Example 134: Synthesis of1-[1-(2-fluorophenethyl)piperdin-4-yl]-6-acetamidomethylindoline

1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and2-fluorophenethyl bromide (220 mg) were treated as in Example 2 to givethe title compound (190 mg) as a whitepowder (yield: 52%).

m.p.: 160-161° C.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.51-1.68(2H, m), 1.81-1.92(2H, m), 2.00(3H, s), 2.20-2.40(2H,m), 2.70-2.89(4H, m), 2.91(2H, t, J=8 Hz), 3.01-3.10(2H, m),3.40-3.48(3H, m), 4.32(2H, d, J=6 Hz), 6.39(1H, s), 6.51(1H, d, J=8 Hz),6.98-7.10(3H, m), 7.18-7.30(2H, m).

FAB-Mass: 396(MH+).

Example 139: Synthesis of1-[1-(3-fluorophenethyl)piperdin-4-yl]-6-acetamidomethylindoline

1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and3-fluorophenethyl bromide (220 mg) were treated as in Example 2 to givethe title compound (210 mg) as white needles (yield: 58%).

m.p.: 161-162° C.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.51-1.68(2H, m), 1.80-1.89(2H, m), 2.00(3H, s), 2.11-2.37(4H,m), 2.65-2.75(2H, m), 2.91(2H, t, J=8 Hz), 3.12-3.29(2H, m),3.40-3.48(3H, m), 4.32 (2H, d, J=6 Hz), 6.38(1H, s), 6.51(1H, d, J=8Hz), 6.98-6.98(2H, m), 7.00-7.05(2H, m), 7.21-7.30(1H, m).

FAB-Mass: 396(MH+).

Example 136: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-hydroxymethylindoline

A 2.5 M solution (100 ml) of n-butyllithium in hexane was added dropwiseat −78° C. into a solution (2 l) of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (80 g) intetrahydrofuran over 15 min. After 10 min, dimethylformamide (23.2 ml)was added thereto and the resultant mixture was warmed to roomtemperature. Next, a saturated aqueous solution of ammonium chloride(400 ml) and ethyl acetate (1 l) were added thereto and the layers wereseparated. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. To theresulting reside were added ethanol (240 ml) and sodium borohydride (7.6g) and the resultant mixture was stirred at room temperature for 1 hr.After adding ice water (480 ml) to the reaction solution, the resultingcrystals were collected by filtration, washed with water and air-driedat 50° C. over day and night to give the title compound (about 71 g) asa yellow powder. A portion of this crude product was purified by silicagel column chromatography (ethyl acetate/methanol system) followed byconversion into a hydrochloride in a conventional manner to give thehydrochloride of the title compound as a pale purple powder.

m.p. (hydrochloride): 190° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90(2H, m), 1.99-2.11(2H, m), 2.81-2.90(2H, m),3.02-3.13(4H, m), 3.20-3.29(2H, m), 3.31(2H, t, J=8 Hz), 3.68-3.63(2H,m) 3.70-3.80(1H, m), 4.38(2H, s), 6.30-6.37(2H, m), 6.96(1H, d, J=8 Hz),7.12-7.20(2H, m), 7.30-7.36(2H, m), 10.60(1H, br-s).

FAB-Mass: 355(MH+).

Example 137: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-(1-hydroxyethyl)indoline

Sodium borohydride (0.03 g) was added to a solution (5 ml) of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetylindoline (0.17 g) inethanol and the resultant mixture was stirred at room temperatureovernight. Then ethyl acetate and water were added to the reactionsolution and the layers were separated. The organic layer was washedwith brine and dried over anhydrous magnesium sulfate. Then the residuewas purified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (150 mg) as a colorless oil (yield:89%).

To a solution of this oily substance in acetone, oxalic acid (37 mg) wasadded to give the oxalate (140 mg) of the title compound as a graypowder.

m.p. (oxalate): 113-116° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.28(3H, d, J=6 Hz), 1.84-2.05(4H, m), 2.84(2H, t, J=8 Hz),3.00-3.35(8H, m), 3.55-3.68(2H, m), 3.70-3.80(1H, m) 4.61(1H, q, J=6Hz), 6.52-6.54(2H, m), 6.94(1H, d, J=8 Hz), 7.16-7.21(2H, m),7.32-7.36(2H, m).

FAB-Mass: 369(MH+).

Example 138: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(1-hydroxypropyl)indoline

A 3 M solution (1.4 ml) of ethylmagnesium in ether was added dropwise at−78° C. into a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (1.0 g) intetrahydrofuran (30 ml) and the resultant mixture was allowed to warm toroom temperature. Then a saturated aqueous solution of ammonium chlorideand ethyl acetate were added to the reaction solution and the layerswere separated. The organic layer was washed with brine and dried overmagnesium sulfate. After removing the solvent, the residue was purifiedby NH-silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (710 mg) as a colorless oil (yield: 66%).

To a solution of this oil (200 mg) in acetone, oxalic acid (47 mg) wasadded to give the oxalate (150 mg) of the title compound as a pale brownpowder.

m.p. (oxalate): 106-108° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 0.80(3H, t, J=7 Hz), 1.50-1.61(2H, m), 1.80-1.95(4H, m), 2.85(2H,t, J=8 Hz), 2.95-3.25(6H, m), 3.31(2H, t, J=8 Hz), 3.51-3.62(2H, m),3.66-3.78(1H, m), 4.32(1H, t, J=6 Hz), 6.49-6.51(2H, m), 6.94(1H, d, J=8Hz), 7.16-7.21(2H, m), 7.31-7.35(2H, m).

FAB-Mass: 383(MH+).

Example 139: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(1-hydroxy-1-methylethyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.75 g), a 2.5M solution (1.1 ml) of n-butyllithium in hexane and acetone (0.16 g)were treated as in Example 130 to give the oxalate (250 mg) of the titlecompound as a pale yellow powder (yield: 35%).

m.p. (oxalate): 179-182° C.

¹H-NMR (400 MHz, DMSO-d₆)

δ(ppm) 1.38(6H, s), 1.81-1.90(4H, m), 2.83 (2H, t, J=8 Hz),2.91-3.04(4H, m), 3.11-3.20(2H, m), 3.30(2H, t, J=8 Hz), 3.50-3.59 (2H,m), 3.66-3.74 (1H, m), 6.63-6.65(2H, m), 6.92 (1H, d, J=8 Hz),7.15-7.20(2H, m), 7.31-7.35(2H, m).

FAB-Mass: 383(MH+).

Example 140: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(1-hydroxycyclobutyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.5 g), a 2.5 Msolution (0.8 ml) of n-butyllithium in hexane and cyclobutanone (0.14ml) were treated as in Example 130 to give the hydrochloride (150 mg) ofthe title compound as a white powder (yield: 29%).

m.p. (hydrochloride): 172-175° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.53-1.64(1H, m), 1.82-1.94(3H, m), 1.96-2.09(2H, m),2.16-2.26(2H, m), 2.31-2.40(2H, m), 2.87(2H, t, J=8 Hz), 3.00-3.44(9H,m), 3.60-3.70(2H, m), 6.64(1H, s), 6.72(1H, d, J=8 Hz), 6.99 (1H, d, J=8Hz), 7.16-7.22 (2H, m), 7. 32-7.36 (2H, m)

FAB-Mass: 395(MH+).

Example 141: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(1hydroxycyclopentyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.5 g), a 2.5 Msolution (0.8 ml) of n-butyllithium in hexane and cyclopentanone (0.17ml) were treated as in Example 130 to give the hydrochloride (240 mg) ofthe title compound as a white powder (yield: 45%).

m.p. (hydrochloride): 191-194° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.64-2.00(12H, m), 2.81(2H, t, J=8 Hz), 2.96-3.04(2H, m),3.06-3.16(2H, m)3.20-3.31(2H, m), 3.34-3.78(5H, m), 6.59(1H, s),6.64(1H, d, J=8 Hz), 6.90(1H, d, J=8 Hz), 7.11-7.19(2H, m),7.30-7.38(2H, m).

FAB-Mass: 409(MH+).

Example 142: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6chloromethylindoline

Conc. hydrochloric acid (280 ml) was added to1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline (about70 g) and the resultant mixture was stirred at 80° C. for a day. Underice cooling, the reaction solution was neutralized with a conc. aqueoussolution of sodium hydroxide followed by addition of ethyl acetate (200ml). The resulting crystals were collected by filtration and dissolvedin ethyl acetate (500 ml) and a 5 N aqueous solution (500 ml) of sodiumhydroxide and the layers were separated. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to give the title compound (70 g) as a paleyellow powder (yield: 94%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.76-1.90(4H, m), 2.10-2.26(2H, m), 2.58-2.70(2H, m),2.78-2.90(2H, m), 2.94(2H, t, J=8 Hz), 3.10-3.24(2H, m), 3.36-3.51(1H,m), 3.43(2H, t, J=8 Hz), 4.53(2H, s), 6.40(1H, s), 6.60(1H, d, J=8 Hz),6.95-7.02(3H, m), 7.14-7.19(2H, m).Example 143: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-fluoromethylindoline

Diethylaminosulfatrifluoride (DAST, 160 mg) was added dropwise at −78°C. into a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline (300 mg)inmethylene chloride (10 ml) and the resultant mixture was stirred for 1hr. Then a saturated aqueous solution of sodium bicarbonate and ethylacetate were added thereto and the layers were separated. The organiclayer was dried over anhydrous magnesium sulfate and the obtainedresidue was purified by NH-silica gel column chromatography(hexane/ethyl acetate system) followed by conversion into ahydrochloride in a conventional manner to give the hydrochloride (100mg) of the title compound as a white powder (yield: 30%).

m.p. (hydrochloride) 190° C. (decomp.)

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.84-1.93 (2H, m), 2.01-2.14 (2H, m), 2.87-2.95 (2H, m),3.00-3.16(4H, m), 3.21-3.30(4H, m), 3.37(2H, t, J=8 Hz), 3.59-3.68(2H,m), 3.73-3.83(1H, m), 5.28(2H, d, J=22 Hz), 6.60-6.63(2H, m), 7.05(1H,d, J=8 Hz), 7.16-7.21(2H, m), 7.33-7.36(2H, m), 10.70(1H, br-s).

FAB-Mass: 357 (MH+).

Example 144: Synthesis of1-[1-(4-fluoropheneyl)piperdin-4-yl]-6-(1-fluoroethyl)indoline

Diethylaminosulfatrifluoride (DAST, 220 mg) was added dropwise at −78°C. into a solution (20 ml) of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyethyl)indoline (400mg) in methylene chloride and the resultant mixture was stirred for 1hr. Then a saturated aqueous solution of sodium bicarbonate andchloroform were added thereto and the layers were separated. The organiclayer was dried over anhydrous magnesium sulfate and the resultingresidue was purified by silica gel column chromatography (hexane/ethylacetate system) followed by conversion into a hydrochloride in aconventional manner to give the hydrochloride (100 mg) of the titlecompound as a white hygroscopic amorphous solid (yield: 23%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.55(3H, dd, J=24, 6 Hz), 1.82-1.92(2H, m), 1.96-2.10(2H, m),2.81-2.93(2H, m), 3.01-3.18(4H, m), 3.22-3.49(4H, m), 3.59-3.69(2H, m),3.71-3.85(1H, m), 5.57(1H, dq, J=48, 6 Hz), 6.54-6.61(2H, m),6.98-7.04(1H, m), 7.18-7.21(2H, m), 7.32-7.40(2H, m).

FAB-Mass: 371(MH+).

Example 145: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-cyanomethylindoline

Dimethyl sulfoxide (500 ml) and sodium cyanide (9.8 g) were added to1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (about 70g) and the resultant mixture was stirred at 50° C. for 2 hr. Next, icewater (500 ml) was added to the reaction solution followed by vigorouslystirring. The resulting crystals were collected by filtration, washedwith water and air-dried at 80° C. to give the title compound (67 g) asa pale yellow powder (yield: 93%).

A portion of this product was purified by silica gel columnchromatography (ethyl acetate/hexane system) followed by conversion intoa hydrochloride in a conventional manner to give the hydrochloride ofthe title compound as a white powder.

m.p. (hydrochloride): 211-214° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-1.91(2H, m), 1.99-2.12(2H, m), 2.90(2H, t, J=8 Hz),3.00-3.19(4H, m), 3.21-3.32(2H, m), 3.35(2H, t, J=8 Hz) 3.60-3.80(3H,m), 3.90(2H, s), 6.49(1H, s), 6.51(1H, d, J=8 Hz) 7.01(1H, d, J=8 Hz),7.13-7.21(2H, m), 7.30-7.40(2H, m).

FAB-Mass: 364(MH+)

Example 146: Synthesis of1-[1-(4-fluoropenethyl)piperdin-4yl]-6-carboxymethylindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-cyanomethylindoline (about 67g) was dissolved in water (134 ml) and conc. sulfuric acid (134 ml) andthe resultant solution was heated under reflux for 7 hr. Under icecooling, the pH value of the reaction mixture was adjusted to 10 with aconc. aqueous solution of sodium hydroxide. Then ethyl acetate (300 ml)was added thereto followed by vigorous stirring. After adjusting the pHvalue of the resultant mixture to about 6 with conc. hydrochloric acid,the resulting crystalline precipitates were collected by filtration,washed with water and air-dried at 50° C. over day and night to give thetitle compound (58 g) as a white powder (yield: 76%).

m.p.: 130-132° C.

¹H-NMR (400 MHz, DMSO-d₆)

δ(ppm) 1.53-1.73(4H, m) 2.70-2.90(4H, m), 3.00-3.53(12H, m), 6.31 (1H,s), 6.39 (1H, d, J=8 Hz), 6.90 (1H, d, J=8 Hz) 7.04-7.15(2H, m),7.22-7.30(2H, m).

FAB-Mass: 383 (MH+).

Example 147: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-carbamoylmethylindoline

Crude 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanomethylindoline (230mg) was dissolved in conc. sulfuric acid (5 ml) and the resultantsolution was stirred overnight. The reaction solution was diluted withice water and the pH value thereof was adjusted to 10 under ice coolingwith a conc. aqueous solution of sodium hydroxide. After extracting thereaction solution with ethyl acetate, the organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/ethanol system) followed by conversioninto a hydrochloride in a conventional manner to give the hydrochloride(200 mg) of the title compound as a white hygroscopic amorphous solid(yield: 76%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-1.92(2H, m), 2.02-2.17(2H, m), 2.86(2H, t, J=8 Hz),3.00-3.16(4H, m), 3.21-3.29(2H, m), 3.34(2H, t, J=8 Hz), 3.60-4.10 (5H,m), 6.43-6.51 (2H, m), 6.81 (1H, br-s), 6.95 (1H, d, J=8 Hz),7.16-7.21(2H, m), 7.32-7.39(3H, m).

FAB-Mass: 382(MH+).

Example 148: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(methylcarbamoylmethyl)indoline

Ethyl chlorocarbonate (87 mg) was added at −78° C. to a mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (250mg), triethylamine (81 mg), dimethylformamide (6 ml) and tetrahydrofuran(8 ml). After heating the resultant mixture to −30° C., a 2 N solution(0.4 ml) of methylamine in tetrahydrofuran was added thereto. Theresultant mixture was further warmed to room temperature and stirred foradditional 30 min. Ice water and ethyl acetate were added to the liquidreaction mixture and the layers were separated. The organic layer waswashed successively with water, a saturated aqueous solution of sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/ethanol system) followed byconversion into a hydrochloride in a conventional manner to give thehydrochloride (120 mg) of the title compound as a white hygroscopicamorphous substance (yield: 45%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-1.92(2H, m), 2.00-2.13(2H, m), 2.55(3H, d, J=4 Hz), 2.86(2H,t, J=8 Hz), 2.99-3.16 (4H, m), 3.22-3.30(4H, m) 3.33 (2H, t, J=8 Hz)3.60-3.76 (3H, m), 6.45-6.50 (2H, m) 6.94 (1H, d, J=8 Hz), 7.16-7.22(2H,m), 7.32-7.40(2H, m), 7.84(1H, d, J=4 Hz), 10.53(1H, br-s).

FAB-Mass: 396(MH+).

Example 149: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(ethylcarbamoylmethyl)indoline

Under ice cooling, 1,1′-carbonyldiimidazole (1.0 g) was added to asolution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (2.0 g)in dimethylformamide (40 ml). After stirring the mixture for 2 hr,ethylamine hydrochloride (0.51 g) was added thereto. Then the resultantmixture was allowed to warm to room temperature and stirred foradditional 5 hr. A saturated aqueous solution of sodium bicarbonate andethyl acetate were added to the reaction solution and the layers wereseparated. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. Then theresidue was dissolved in hot toluene (10 ml). After allowing to cool toroom temperature, the resulting crystals were collected by filtration togive the title compound (1.3 g) as a white powder (yield: 56%).

Next, the product was converted into a hydrochloride in a conventionalmanner followed by recrystallization from acetone to give thehydrochloride of the title compound as a white powder.

m.p. (hydrochloride): 161-164° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 0.99(3H, t, J=7 Hz), 1.83-1.93(2H, m), 1.96-2.11(2H, m), 2.85(2H,t, J=8 Hz), 2.98-3.17(6H, m), 3.23-3.39(6H, m), 3.61-3.75(3H, m),6.41-6.48(2H, m), 6.93(1H, d, J=8 Hz), 7.15-7.23(2H, m), 7.30-7.37(2H,m), 7.92(1H, br-s).

FAB-Mass: 410(MH+).

Example150:Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(n-propylcarbamolymethyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (220mg), 1,1′-carbonyldiimidazole (110 mg) and n-propylamine (41 mg) weretreated as in Example 149 to give the title compound (90 mg) as whiteneedles (yield: 37%).

m.p.: 143-145° C.

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 0.83(3H, t, J=7 Hz), 1.42(2H, sextet, J=7 Hz), 1.75-1.79(4H, m),2.10-2.30(2H, m), 2.53-2.71(2H, m), 2.78-2.90(2H, m), 2.95(2H, t, J=8Hz), 3.09-3.21(4H,m), 3.37-3.49(1H, m), 3.42(2H, t, J=8 Hz), 3.50(2H,s), 5.51(1H, br-s), 6.29(1H, s), 6.48(1H, d, J=8 Hz), 6.92-7.01(3H, m),7.12-7.20(2H, m).

FAB-Mass: 424(MH+).

Example 151: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(isopropylcarbamoylmethyl)indoline

Under ice cooling, 1,1′-carbonyldimidazole (15 g) was added to asolution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (30 g)in dimethylformamide (240 ml) and the resultant mixture was stirred for2 hr. After adding isopropylamine (5.6 g), the mixture was warmed toroom temperature and then stirred for additional 2 hr. Next, ice water(240 ml) and ethyl acetate (300 ml) were added to the reaction solutionand the layers were separated. The organic layer was washed successivelywith water, a saturated aqueous solution of sodium bicarbonate andbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in hot ethyl acetate (80ml). After allowing to cool to room temperature, the resulting crystalswere collected by filtration to give the title compound (17.2 g) as awhite powder (yield: 52%).

Next, the product was converted into a hydrochloride in a conventionalmanner followed by recrystallization from ethanol to give thehydrochloride of the title compound as a white powder.

m.p. (hydrochloride): 153-155° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.03(6H, d, J=7 Hz), 1.84-1.92(2H, m), 1.96-2.10(2H, m), 2.85(2H,t, J=8 Hz), 3.01-3.16(4H, m), 3.20-3.38(6H, m), 3.61-3.83(4H, m),6.42-6.46(2H, m), 6.93(1H, d, J=8 Hz), 7.16-7.23(2H, m), 7.31-7.38(2H,m), 7.83(1H, d, J=8 Hz).

FAB-Mass: 424(MH+).

Example 152: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(isobutylcarbamoylmethyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (300mg), 1,1′-carbonyldiimidazole (150 mg) and isobutylamine (69 mg) weretreated as in Example 151 to give the hydrochloride (270 mg) of thetitle compound as white needles (yield: 72%).

m.p. (hydrochloride): 122-124° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 0.81(6H, d, J=7 Hz), 1.66(1H, septet, J=7 Hz), 1.84-1.92(2H, m),2.00-2.15(4H, m), 2.81-2.90(4H, m), 3.02-3.15(2H, m), 3.23-3.38(4H, m),3.44-3.73(5H, m), 6.48-6.53(2H, m), 6.95(1H, d, J=8 Hz), 7.17-7.22(2H,m), 7.29-7.40(2H, m), 7.94(1H, br-s).

FAB-Mass: 438(MH+).

Example 153: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(t-butylcarbamoylmethyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (250mg), 1,1′-carbonyldiimidazole (130 mg) and t-butylamine (58 mg) weretreated as in Example 151 to give the hydrochloride (140 mg) of thetitle compound as a pale brown powder (yield: 45%).

m.p. (hydrochloride): 189-192° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.24(9H, s), 1.84-1.92(2H, m), 2.03-2.16(2H, m), 2.87(2H, t, J=8Hz),3.03-3.15(4H, m), 3.22-3.30(4H, m),3.34(2H, t, J=8 Hz),3.58-3.77(3H, m), 6.47-6.50(2H, m), 6.95(1H, d, J=8 Hz), 7.16-7.21(2H,m), 7.32-7.36(2H, m), 7.58(1H, br-s), 10.69(1H, br-s).

FAB-Mass: 438(MH+).

Example 154: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(cyclopropylcarbamoylmethyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (250mg), 1,1′-carbonyldiimidazole (130 mg) and cyclopropylamine (45 mg) weretreated as in Example 151 to give the title compound (110 mg) as a whitepowder (yield: 40%).

m.p.: 182-184° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.36-0.41(2H, m), 0.69-0.74(2H, m), 1.75-1.90(4H, m),2.10-2.30(2H, m), 2.60-2.71(3H, m), 2.75-2.90(2H, m), 2.94(2H, t, J=8Hz),3.10-3.25(2H, m),3.35-3.48(5H, m), 5.60(1H, br-s), 6.26(1H, s),6.42(1H, d, J=8 Hz), 6.96-7.01(3H, m), 7.15-7.20(2H, m).

FAB-Mass: 422(MH+).

Example 155: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(tetramethylenecarbamoylmethyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (360mg), 1,1′-carbonyldiimidazole (160 mg) and pyrrolidine (70 mg) weretreated as in Example 151 to give the hydrochloride (280 mg) of thetitle compound as a white powder (yield: 60%).

m.p. (hydrochloride): 159-161° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.90-2.04(8H, m), 2.86(2H, t, J=8 Hz),3.00-3.19(4H, m),3.21-3.39(6H, m), 3.42(2H, t, J=8 Hz), 3.61-3.76(3H, m), 6.41(1H, s),6.43(1H, d, J=8 Hz), 6.94(1H, d, J=8 Hz), 7.17-7.22(2H, m),7.30-7.37(2H, m).

FAB-Mass: 436(MH+).

Example 156: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-1-6-propionylaminomethylindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (200 mg),triethylamine (69 mg) and propionyl chloride (63 mg) were treated as inExample 133 to give the hydrochloride (88 mg) of the title compound as apale brown powder (yield: 35%).

m.p. (hydrochloride): 157° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 0.99(3H, t, J=7 Hz), 1.82-2.10(4H, m), 2.10(2H, q, J=7 Hz),2.84(2H, t, J=8 Hz), 2.92-3.14(4H, m), 3.21-3.35(4H, m), 3.59-3.73(3H,m), 4.12(2H, d, J=6 Hz), 6.41(1H, s), 6.44(1H, d, J=8 Hz), 6.94(1H, d,J=8 Hz), 7.15-7.20(2H, m), 7.30-7.35(2H, m), 8.12(1H, t, J=6 Hz).

FAB-Mass: 410(MH+).

Example 157: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(n-butyryl)aminomethylindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (200 mg),triethylamine (69 mg) and n-butyryl chloride (72 mg) were treated as inExample 133 to give the title compound (110 mg) as pale yellow needles(yield: 46%).

m.p.: 153-155° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.96(3H, t, J=7 Hz), 1.68(2H, sextet, J=7 Hz), 1.75-1.83(4H, m),2.10-2.22(2H, m), 2.17(2H, q, J=7 Hz), 2.55-2.70(2H, m), 2.74-2.90(2H,m), 2.93(2H, t, J=8 Hz), 3.05-3.20(2H, m), 3.35-3.45(1H, m), 3.42(2H, t,J=8 Hz), 4.34(2H, d, J=6 Hz), 6.33(1H, s), 6.50(1H, d, J=8 Hz),6.95-7.00(3H, m), 7.10-7.19(2H, m).

FAB-Mass: 424(MH+).

Example 158: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-isobutyrylaminomethylindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (300 mg),triethylamine (80 mg) and isobutyryl chloride (90 mg) were treated as inExample 133 to give the title compound (200 mg) as white needles (yield:58%).

m.p.: 163-165° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.17(6H, d, J=7 Hz), 1.51-1.66(2H, m), 1.75-1.87(2H, m),2.10-2.25(2H, m), 2.36(1H, septet, J=7 Hz), 2.56-2.72(2H, m),2.75-2.95(2H, m), 2.93(2H, t, J=8 Hz), 3.08-3.25(2H, m), 3.35-3.45(1H,m), 3.42(2H, t, J=8 Hz), 4.34(2H, d, J=6 Hz), 6.33(1H, s), 6.50(1H, d,J=8 Hz), 6.96-7.01(3H, m), 7.15-7.19(2H, m).

FAB-Mass: 424(MH+).

Example 159: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-cyclopropanecarboxamindomethylindoline

1-[-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (250 mg)and cyclopropanecarbonyl chloride (81 mg) were treated as in Example 133to give the hydrochloride (100 mg) of the title compound as a whitepowder (yield: 31%).

m.p.: 143-146° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 0.60-0.69(4H, m), 1.55-1.63(1H, m), 1.83-1.90(2H, m),1.99-2.09(2H, m), 2.86(2H, t, J=8 Hz), 3.02-3.16(4H, m), 3.22-3.30(2H,m), 3.31(2H, t, J=8 Hz), 3.60-3.79(3H, m), 4.16(2H, d, J=6 Hz), 6.47(1H,s), 6.48(1H, d, J=8 Hz), 6.98(1H, d, J=8 Hz), 7.16-7.21(2H, m),7.32-7.38(2H, m), 8.43(1H, d, J=6 Hz).

FAB-Mass: 422(MH+).

Example 160: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-methylsulfonylaminomethylindoline

Under ice cooling, methanesulfonyl chloride (78 mg) was added dropwiseinto a solution of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-aminomethylindoline (200 mg)in pyridine (20 ml) and the resultant mixture was stirred for 30 min.After concentrating under reduced pressure, the residue was partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. Then the residue was purified by silica gel columnchromatography (ethyl acetate/ethanol system) followed by conversioninto a hydrochloride in a conventional manner to give the hydrochloride(160 mg) of the title compound as a white hygroscopic amorphous solid(yield: 60%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.91(2H, m), 2.00-2.12(2H, m), 2.78(3H, s), 2.82-2.90(2H,m), 2.97-3.15(4H, m), 3.19-3.30(2H, m), 3.33(2H, t, J=8 Hz),3.58-3.75(3H, m), 4.02(2H, s), 6.53(1H, s), 6.55(1H, d, J=8 Hz),6.98(1H, d, J=8 Hz), 7.14-7.19(2H, m), 7.30-7.34(2H, m), 7.42(1H, br-s),10.70(1H, br-s).

FAB-Mass: 432(MH+).

Example 161: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-ureidomethylindoline

A solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (300 mg)and nitrourea (90 mg) in methanol (10 ml) was heated under reflux for 3hr. After concentrating under reduced pressure, the residue wascrystallized from ethyl acetate. The resulting crystals were dissolvedin ethanol followed by conversion into a hydrochloride to give thehydrochloride (260 mg) of the title compound as a gray hygroscopicamorphous solid (yield: 71%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-2.02(4H, m), 2.84(2H, t, J=8 Hz), 2.98-3.16(4H, m),3.20-3.74(7H, m), 4.04(2H, br-s), 6.42(1H, s), 6.45(1H, d, J=8 Hz),6.94(1H, d, J=8 Hz), 7.15-7.20(2H, m), 7.31-7.34(2H, m)

FAB-Mass: 397(MH+).

Example 162: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-N-methylaminomethylindoline

Ethyl chlorocarbonate (300 mg) was added dropwise at room temperatureinto a solution of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-aminomethylindoline (800 mg)and triethylamine (290 mg) in methylene chloride (20 ml) and theresultant mixture was stirred for 90 min. After concentrating underreduced pressure, the residue was partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was then added to a suspension of lithium aluminum hydride (260mg) in tetrahydrofuran (20 ml) and the resultant mixture was heatedunder reflux for 1 hr. Under ice water cooling, water (0.26 ml), a 5 Naqueous solution (0.78 ml) of sodium hydroxide and further water (0.26ml) were carefully added dropwise to the reaction solution followed byvigorous stirring. The resulting precipitate was filtered off and thefiltrate was concentrated under reduced pressure. The residue waspurified by NH-silica gel column chromatography (ethyl acetate/ethanolsystem) to give the title compound (700 mg) as an oil (yield: 83%).

A portion of this product was converted into a hydrochloride in aconventional manner to give the hydrochloride of the title compound as adark red hygroscopic amorphous solid.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.90-1.98(2H, m), 2.06-2.20(2H, m), 2.48(3H, s), 2.89(2H, t, J=8Hz), 2.99-3.12(4H, m), 3.22-3.31(2H, m), 3.35(2H, t, J=8 Hz),3.58-3.68(3H, m), 3.95(2H, br-s), 6.64(1H, d, J=8 Hz), 6.87(1H, s),7.03(1H, d, J=8 Hz), 7.10-7.19(2H, m), 7.30-7.34(2H, m), 9.22(2H, br-s),10.79(1H, br-s).

FAB-Mass: 368(MH+).

Example 163: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-N-methylacetamidomethylindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-N-methylaminomethylindoline(540 mg), triethylamine (200 mg) and acetyl chloride (150 mg) weretreated as in Example 133 to give the hydrochloride (330 mg) of thetitle compound as a white hygroscopic amorphous solid (yield: 50%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.89(2H, m), 1.92-2.06(2H, m), 2.02(3H, s), 2.75(1.5H, s),2.85(1.5H, s), 2.80-2.90(2H, m), 3.00-3.14(4H, m), 3.21-3.36(4H, m),3.58-3.73(3H, m), 4.35(1H, s), 4.40(1H, s), 6.32(0.5H, s), 6.36(0.5H,s), 6.37(0.5H, d, J=8 Hz), 6.40(0.5H, d, J=8 Hz), 6.95(0.5H, d, J=8 Hz),6.99(0.5H, d, J=8 Hz), 7.14-7.19(2H, m), 7.30-7.34(2H, m).

FAB-Mass: 410(MH+).

Example 164: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(N-methylsulfamoylmethyl)indoline

6-(N-Methylsulfamoylmethyl)indoline (100 mg),1-(4-fluorophenethyl)-4-piperidone (150 mg), acetic acid (120 mg) andtriacetoxylated sodium borohydride (140 mg) were treated as in Example 1to give the title compound (100 mg) as white prisms (yield: 53%).

m.p.: 162-164° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.70-1.89(4H, m), 2.07-2.20(2H, m), 2.55-2.64(2H, m), 2.71(3H, d,J=6 Hz), 2.75-2.86(2H, m), 2.95(2H, t, J=8 Hz), 3.08-3.15(2H, m),3.37-3.50(3H, m), 4.10-4.30(1H, m), 4.18(2H, s), 6.43(1H, s), 6.54(1H,d, J=8 Hz), 6.91-7.03(3H, m), 7.11-7.20(2H, m).

FAB-Mass: 432(MH+).

Example 165: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(1-acetamidoethlyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyethyl)indoline (300mg) was treated as in Example 90 to give the hydrochloride (80 mg) ofthe title compound as a pale yellow hygroscopic amorphous solid (yield:22%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.29(3H, d, J=7 Hz), 1.82(3H, s), 1.83-1.93(2H, m), 2.00-2.15(2H,m), 2.84(2H, t, J=8 Hz), 3.01-3.15(4H, m), 3.20-3.35(2H, m), 3.32(2H, t,J=8 Hz), 3.60-3.77(3H, m), 4.80(1H, quintet, J=7 Hz), 6.51-6.53(2H, m),6.95(1H, d, J=8 Hz), 7.17-7.21(2H, m), 7.32-7.37(2H, m), 8.19(1H, d, J=8Hz).

FAB-Mass: 410(MH+).

Example 166: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoethylindoline

A mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanomethylindoline (0.25 g),platinum oxide (50 mg), 5 N hydrochloric acid (1.0 ml) and methanol (20ml) was catalytically reduced under hydrogen atmosphere of 3 atm. After4 hr, the catalyst was filtered off and the filtrate was concentratedunder reduced pressure. To the resulting residue were added a 5 Naqueous solution (10 ml) of sodium hydroxide, acetyl chloride (0.2 ml)and methylene chloride (20 ml) and the resultant mixture was stirredvigorously for 1 hr. Next, it was diluted with water and chloroform andthe layers were separatetd. The organic layer was washed with brine anddried over anhydrous magnesium sulfate. The residue was purified byNH-silica gel column chromatography (hexane/ethyl acetate system)followed by conversion into an oxalate in a conventional manner to givethe oxalate (90 mg) of the title compound as a brown hygroscopicamorphous solid (yield: 26%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80-1.94(4H, m), 2.08(3H, s), 2.58(2H, t, J=7 Hz), 2.84(2H, t,J=8 Hz), 2.93-3.07(4H, m), 3.15-3.24(4H, m), 3.31(2H, t, J=8 Hz),3.51-3.59(2H, m), 3.64-3.74(1H, m), 6.36(1H, s), 6.39(1H, d, J=8 Hz),7.15-7.21(2H, m), 7.31-7.39(2H, m), 7.88(1H, t, J=6 Hz).

FAB-Mass: 410(MH+).

Example 167: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[(piperidin-4-yl)methyl]indoline

A mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-4-pyridylmethyl)indoline(1.2 g), 10% palladium-carbon (600 mg), 5 N hydrochloric acid (2.9 ml)and ethanol (30 ml) was catalytically reduced under hydrogen atmosphereof 3 atm. After 7 hr, platinum oxide (150 mg) was added thereto and thecatalytic reduction was continued for additional 2 hr. Then the catalystwas filtered off and the filtrate was concentrated under reducedpressure. The resulting residue was diluted with a saturated aqueoussolution of sodium bicarbonate and ethyl acetate and the layers wereseparated. The organic layer was washed with brine and dried overanhydrous magnesium sulfate. The residue was purified by NH-silica gelcolumn chromatography (ethanol/ethyl acetate system) followed byconversion into a hydrochloride in a conventional manner to give thehydrochloride (510 mg) of the title compound as a white powder (yield:33%).

m.p. (hydrochloride): 162-165° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.27-1.40(2H, m), 1.65-1.91(5H, m), 2.03-2.17(2H, m),2.38-2.44(2H, m), 2.51-2.84(2H, m), 2.84(2H, t, J=8 Hz), 3.01-3.45(10H,m), 3.59-3.76(3H, m), 3.36-3.39(2H, m), 6.93(1H, d, J=8 Hz),7.16-7.21(2H, m), 7.32-7.36(2H, m), 8.68(1H, br-s), 8.85(1H, br-s),10.79(1H, br-s).

FAB-Mass: 422(MH+).

Example 168: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(1-acetylpiperidin-4-yl)methyllindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[(piperidin-4-yl)methyl]indoline(100 mg) and acetyl chloride (0.1 ml) were treated as in Example 133 togive the hydrochloride (50 mg) of the title compound as a pale yellowhygroscopic amorphous solid (yield: 45%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 0.87-1.12(2H, m), 1.50-1.78(3H, m), 1.82-1.91(2H, m), 1.96(3H,s), 2.00-2.16(2H, m), 2.36-2.45(2H, m), 2.81-2.98(4H, m), 3.00-3.16(4H,m), 3.20-3.38(4H, m), 3.57-3.80(4H, m), 4.26-4.36(1H, m), 6.40-6.42(2H,m), 6.94(1H, d, J=8 Hz), 7.16-7.21(2H, m), 7.32-7.36(2H, m).

FAB-Mass: 464(MH+).

Example 169: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[(1-ethylpiperidin-4-yl)methyllindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[(piperidin-4-yl)methyl]indoline(190 mg) and ethyl iodide (84 mg) were treated as in Example 2 to givethe hydrochloride (50 mg) of the title compound as a pale brownhygroscopic amorphous solid (yield: 21%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.22(3H, t, J=7 Hz), 1.43-1.56(2H, m), 1.68-1.70(5H, m),2.04-2.19(2H, m), 2.38-2.45(2H, m), 2.69-2.83(2H, m), 2.85(2H, t, J=8Hz), 2.95-3.18(6H, m), 3.20-3.31(2H, m), 3.32(2H, t, J=8 Hz),3.35-3.43(2H, m), 3.57-3.70(3H, m), 6.37-6.41 (2H, m), 6.94(1H, d, J=8Hz), 7.16-7.22(2H, m), 7.30-7.37(2H, m), 10.17(1H, br-s), 10.80(1H,br-s).

FAB-Mass: 450(MH+).

Example 170: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[(1-methylpiperidin-4-yl)methylindoline

A mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(piperidin-4-yl)methyl]indoline(200 mg), formamide (40 mg), formic acid (44 mg), water (5 ml) andmethanol (5 ml) was heated under reflux overnight. Then, a saturatedaqueous solution of sodium bicarbonate and ethyl acetate were addedthereto and the layers were separated. The organic layer was washed withbrine and dried over anhydrous magnesium sulfate. Then the residue waspurified by NH-silica gel column chromatography (hexane/ethyl acetatesystem) followed by conversion into a hydrochloride in a conventionalmanner to give the hydrochloride (60 mg) of the title compound as a paleyellow hygroscopic amorphous solid (yield: 25%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.40-1.54(2H, m), 1.63-1.76(3H, m), 1.82-1.90(2H, m),2.05-2.18(2H, m), 2.38-2.44(2H, m), 2.51(3H, s), 2.64-2.65(2H, m),2.80-2.90(2H, m), 3.01-3.17(4H, m), 3.20-3.39(6H, m), 3.58-3.70(3H, m),6.38-6.42(2H, m), 6.94(1H, d, J=8 Hz), 7.16-7.21(2H, m), 7.32-7.36(2H,m), 10.34(1H, br-s), 10.85(1H, br-s).

FAB-Mass: 436(MH+).

Example 171: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyridyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.405 g) and2-tributylstannylpyridine (1.85 g) synthesized in accordance with themethod described in Tetrahedron Lett., 4407 (1986). were treated as inProduction Example 13-2 to give the ti tle compound (0.234 g) as a paleyellow oil (yield: 46.6%).

Next, oxalic acid (52 mg) was added to the above product to give anoxalate followed by recrystallization from acetone to give the oxalate(0.254 g) of the title compound as orange crystals.

m.p. (oxalate): 182° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.92(4H, m), 2.95(2H, t, J=8.4 Hz), 2.99(2H, m), 3.04(2H, m),3.17(2H, m), 3.40(2H, t, J=8.4 Hz), 3.56(2H, br-d), 3.86(1H, m),7.17(4H, m), 7.32(4H, m), 7.85(2H, m), 8.62(1H, d, J=4.4 Hz).

FAB-Mass: 402(MH+).

Example 172: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-thiazolyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.56 g) and2-tributylstannylthiazole (2.778 g) synthesized in accordance with themethod described in Synthesis, 757 (1986). were treated as in ProductionExample 13-2 to give the title compound (0.017 g) as pale yellowcrystals (yield: 3.0%).

Next, oxalic acid (2 mg) was added to the above product to give anoxalate followed by recrystallization from acetone to give the oxalateof the title compound as yellow crystals.

m.p. (oxalate): 170° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.90(4H, m), 2.95(2H, t, J=8.4 Hz), 2.98(2H, m), 3.04(2H, m),3.16(2H, m), 3.42(2H, t, J=8.4 Hz), 3.56(2H, m), 3.85(1H, m), 7.06(1H,s), 7.13(2H, m), 7.33(2H, m), 7.71(1H, d, J=3.2 Hz), 7.86(1H, d, J=3.2Hz).

FAB-Mass: 408(MH+).

Example 173: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(1-methylpyrrol-2-yl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.1 g) and1-methyl-2-tributylstannylpyrrole (0.37 g) synthesized in accordancewith the method described in Tetrahedron Lett., 4407 (1986). weretreated as in Production Example 13-2 to give the title compound (0.016g) as a yellow oil (yield: 15.8%).

Next, oxalic acid (2 mg) was added to the above product to give anoxalate followed by recrystallization from acetone to give the oxalateof the title compound as yellow crystals.

m.p. (oxalate): 118° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83(4H, m), 2.79(2H, m), 2.90(2H, t, J=8.4 Hz), 2.92(2H, m),3.02(2H, m), 3.37(2H, t, J=8.4 Hz), 3.41(2H, m), 3.60(3H, s), 3.68(1H,m), 6.01(1H, dd, J=2.4, 3.6 Hz), 6.05(1H, dd, J=2.0, 3.6 Hz), 6.51(1H,d, J=1.2 Hz), 6.58(1H, dd, J=1.2, 7.6 Hz), 6.78(1H, dd, J=2.0, 2.4 Hz),7.04(1H, d, J=7.6 Hz), 7.15(2H, m), 7.31(2H, m).

ESI-Mass: 404.2(MH+).

Example 174: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)methyl]indoline

2-Bromopyridine (0.16 ml),1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (0.5 g) anddiethyl ether employed as the solvent were treated as in Example 93 togive the title compound (0.344 g) as a yellow oil (yield: 56.1%).

To a 50 mg portion of the above product was added oxalic acid (10 mg) togive the oxalate of the title compound.

m.p. (oxalate): 105° C.

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.72-1.81(4H, m), 2.08-2.19(2H, m), 2.57-5.61(2H, m),2.78-2.82(2H, m), 2.91(1H, t, J=8.4 Hz), 3.10(2H, br-t), 3.38(2H, t,J=8.4 Hz), 3.40(1H, m), 5.21(1H, d, J=4.0 Hz), 5.66(1H, d, J=4.0 Hz),6.43(1H, d, J=1.2 Hz), 6.56(1H, dd, J=1.2, 7.2 Hz), 6.95-6.99(3H, m),7.13-7.26(4H, m), 7.60(1H, ddd, J=1.6, 7.2, 8.8 Hz), 8.54(1H, ddd,J=0.8, 1.6, 4.0 Hz).

ESI-Mass: 432.2(MH+).

Example 175: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-(2-pyridyl)methyl]indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)methyl]indoline(0.321 g) was dissolved in ethanol (86.4 ml) f ollowed by the additionof 1 N hydrochloric acid (3.7 ml) and palladium carbon. Then theresultant mixture was catalytically reduced under atmospheric pressurefor 3 hr. After filtering off the catalyst, the filtrate wasconcentrated under reduced pressure. To the residue were added asaturated aqueous solution of sodium bicarbonate and ethyl acetate andthe layers were separated. The organic layer was washed with brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. Then the residue was purified by NH-silica gel columnchromatography (hexane/ethyl acetate-methanol system) to give the titlecompound (0.076 g) as ayellow oil (yield: 24.6%).

Then oxalic acid (16.5 mg) was added to the above product to give theoxalate of the title compound as a yellow hygroscopic amorphous solid.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.77(4H, m), 2.67(2H, m), 2.81(2H, t, J=8.2 Hz), 2.87-2.93(4H,m), 3.30(2H, t, J=8.2 Hz), 3.36(2H, br-d),3.95(1H, m), 4.17(2H, s),6.42-6.44(2H, m), 6.91(1H, d, J=7.5 Hz), 7.12-7.21(4H, m), 7.29-7.32(2H,m), 7.67(1H, ddd, J=1.8, 6.0, 6.0 Hz), 8.46(1H, dd, J=0.8, 4.8 Hz).

FAB-Mass: 416(MH+).

Example 176: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-hydroxy-1-(3-pyridyl)methyl]indoline

3-Bromopyridine (0.44 ml),1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (0.4 g) anddiethyl ether employed as the solvent were treated as in Example 93 togive the title compound (0.337 g) as a yellow oil (yield: 68.8%).

Then oxalic acid was added to the above product to give the oxalate ofthe title compound as an amorphous solid.

m.p. (oxalate): 110-113° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.88(4H, m), 2.83(2H, t, J=8.5 Hz), 3.01(4H, m), 3.19(2H, m),3.30(2H, t, J=8.5 Hz), 3.57(2H, m), 3.71(1H, m), 5.65(1H, s), 6.56(1H,d, J=7.6 Hz), 6.59(1H, s), 6.95(1H, d, J=7.6 Hz), 7.18(2H, m), 7.32(3H,m), 7.70(1H, ddd, J=1.6, 2.0, 6.0 Hz), 8.40(1H, dd, J=1.6, 5.2 Hz),8.57(1H, d, J=2.0 Hz).

ESI-Mass: 432.2(MH+).

Example 177: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-(3-pyridyl)methyl]indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(3-pyridyl)methyl]indoline(0.1 g) was treated as in Example 175 to give the title compound (0.018g) as a colorless oil (yield: 18.7%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.79(4H, m), 2.14(2H, m), 2.61(2H, m), 2.81(2H, m), 2.91(2H, t,J=8.4 Hz), 3.13(2H, br-d), 3.25(1H, m), 3.40(2H, t, J=8.4 Hz), 3.88(2H,s), 6.19(1H, d, J=1.2 Hz), 6.41(1H, dd, J=1.2, 7.4 Hz), 6.97(3H, m),7.17(3H, m), 7.47(1H, m), 8.44(1H, dd, J=1.2, 4.8 Hz), 8.51(1H, d, J=1.2Hz).

ESI-Mass: 416.2(MH+).

Next, oxalic acid (5 mg) was added to the above product to give theoxalate of the title compound as an amorphous solid.Example 178: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(1-hydroxy-4-pyridylmethyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (700 mg), a 2.5M solution (1.0 ml) of n-butyllithium in hexane and4-pyridinecarbaldehyde (280 mg) were treated as in Example 130 to givethe oxalate (130 mg) of the title compound as a brown hygroscopicamorphous substance (yield: 15%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.75-1.93(4H, m), 2.83(2H, t, J=8 Hz), 2.91-3.02(4H, m),3.11-3.19(2H, m), 3.30(2H, t, J=8 Hz), 3.48-3.57(2H, m), 3.61-3.71(1H,m), 5.57(1H, s), 6.55-6.57(2H, m), 6.94(1H, d, J=8 Hz), 7.15-7.20(2H,m), 7.31-7.36(4H, m), 8.45-8.47(2H, m).

FAB-Mass: 432(MH+).

Example 179: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(4-pyridylmethyl)indoline

A mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-4-pyridylmethyl)indoline(350 mg), 10% palladium carbon (200 mg), 5 N hydrochloric acid (0.8 ml)and ethanol (20 ml) was catalytically reduced under hydrogen atmosphereof 3 atm. After 5 hr, the catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. Then the residue was diluted with asaturated aqueous solution of sodium bicarbonate and ethyl acetate andthe layers were separated. The organic layer was washed with brine anddried over anhydrous magnesium sulfate. Then the residue was purified byNH-silica gel column chromatography (hexane/ethyl acetate system)followed by conversion into an oxalate in a conventional manner to givethe oxalate (190 mg) of the title compound as a white powder (yield:46%).

m.p. (oxalate): 195-197° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.79-1.94(4H, m), 2.84(2H, t, J=8 Hz), 2.92-2.90(4H, m),3.11-3.19(2H, m), 3.32(2H, t, J=8 Hz), 3.48-3.56(2H, m), 3.59-3.69(1H,m), 3.83(2H, s), 6.41-6.43(2H, m), 6.94(1H, d, J=8 Hz), 7.15-7.22(4H,m), 7.30-7.34(2H, m), 8.42-8.44(2H, m).

FAB-Mass: 416(MH+).

Example 180: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(2-pyridylcarbonyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)methyl]indoline(0.895 g) was treated in accordance with the method described in J. Org.Chem., 2899 (1993). to give the title compound (0.357 g) as a yellow oil(yield: 40.1%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.81(4H, m), 2.18(2H, m), 2.60(2H, m), 2.80(2H, m), 3.01(2H, t,J=8.4 Hz), 3.11(2H, m), 3.47(2H, t, J=8.4 Hz), 3.51(1H, m), 6.97(2H, m),7.02(1H, d, J=0.6 Hz), 7.09(1H, d, J=7.2 Hz), 7.17(3H, m), 7.45(1H, ddd,J=1.4, 5.0, 7.6 Hz), 7.87(1H, ddd, J=1.8, 7.6, 7.6 Hz), 7.93(1H, ddd,J=0.8, 1.4, 7.6 Hz), 8.71(1H, ddd, J=0.8, 1.8, 5.0 Hz).Example 181: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)ethyl]indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(2-pyridylcarbonyl)indoline(0.074 g) was dissolved in tetrahydrofuran (1.0 ml). To the resultantsolution was added at −78° C. a 3.0 M solution of methylmagnesiumbromide in diethyl ether and the resultant mixture was stirred for 1 hr.Next, water and ethyl acetate were added thereto and the layers wereseparated. The organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by NH-silica gel column chromatography (hexane/ethylacetate-methanol system) to give the title compound (0.029 g) as ayellow oil (yield: 37.8%).

Next, oxalic acid (6 mg) was added to the above product to give theoxalate of the title compound as a yellow amorphous solid.

m.p. (oxalate): 98-108° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.84(4H, m), 2.80(2H, t, J=8.4 Hz), 2.99(2H, m), 3.11(2H, m),3.24(2H, m), 3.28(2H, t, J=8.4 Hz), 3.59(2H, m), 3.70(1H, m), 6.61(1H,d, J=7.4 Hz), 6.69(1H, s), 6.88(1H, d, J=7.4 Hz), 7.19(3H, m), 7.36(2H,m), 7.58(1H, m), 7.71(1H, m), 8.46(1H, m).

ESI-Mass: 446.3(MH+).

Example 182-1: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)-2-trimethylsilylethyl]indoline

(wherein TMS means trimethylsilyl.)

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)ethyl]indoline(0.357 g) was treated in accordance with the method described inSynthesis, 384 (1984). to give the title compound (0.250 g) as a yellowoil (yield: 58.3%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) −0.75(9H, s), 1.75(4H, m), 2.13(2H, m), 2.58(2H, m), 2.78(2H, m),2.87(3H, t, J=8.4 Hz), 3.09(2H, m), 3.36(2H, t, J=8.4 Hz), 3.43(1H, m),5.99(2H, s), 6.64(1H, d, J=1.2 Hz), 6.76(1H, dd, J=1.2, 7.6 Hz),6.94(1H, d, J=7.6 Hz), 6.97(2H, m), 7.11(1H, ddd, J=0.8, 4.8, 7.6 Hz),7.15(2H, m), 7.39(1H, ddd, J=0.8, 0.8, 8.0 Hz), 7.59(1H, ddd, J=1.6,7.6, 8.0 Hz), 8.45(1H, ddd, J=0.8, 1.6, 4.8 Hz).Example 182-2: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-(2-pyridyl)vinyl]indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)-2-trimethylsilylethylindoline(0.250 g) was treated in accordance with the method described in J. Am.Chem. Soc., 1464 (1975). to give the title compound (0.138 g) as ayellow oil (yield: 66.6%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.80(4H, m), 2.07(2H, m), 2.56(2H, m), 2.77(2H, m), 2.97(2H, t,J=8.4 Hz), 3.08(2H, br-d), 3.36(1H, m), 3.43(2H, t, J=8.4 Hz), 5.40(1H,d, J=1.8 Hz), 5.98(1H, d, J=1.8 Hz), 6.37(1H, d, J=1.2 Hz), 6.57(1H, dd,J=1.2, 7.6 Hz), 6.96(2H, m), 7.03(1H, d, J=7.6 Hz), 7.14(2H, m),7.20(1H, ddd, 0.6, 5.0, 7.6 Hz), 7.27(1H, ddd, 0.4, 0.6, 7.2 Hz),7.60(1H, ddd, 2.0, 7.2, 7.6 Hz), 8.64(1H, ddd, 0.4, 2.0, 5.0 Hz).Example 182-3: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-(2-pyridyl)ethyl]indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-(2-pyridyl)vinyl]indoline(0.138 g) was treated as in Production Example 59-2 to give the titlecompound (0.110 g) as a yellow oil (yield: 79.3%).

Next, oxalic acid (23 mg) was added to the above product to give theoxalate of the title compound as an amorphous solid.

m.p. (oxalate): 95-102° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.58(3H, d, J=7.2 Hz), 1.83(4H, m), 2.81(2H, t, J=8.0 Hz),2.96(2H, m), 3.16(2H, m), 3.29(2H, t, J=8.0 Hz), 3.53(2H, m), 3.67(1H,m), 4.14(1H, q, J=7.2 Hz), 6.48(2H, m), 6.91(1H, d, J=7.6 Hz), 7.18(4H,m), 7.33(2H, m), 7.66(1H, ddd, J=1.6, 7.6, 7.6 Hz), 8.48(1H, m).

ESI-Mass: 430.3(MH+).

Example 183: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(3-pyridylcarbonyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(3-pyridyl)methyl]indoline(0.121 g) was treated in accordance with the method described in J. Org.Chem., 2899 (1993). to give the title compound (0.009 g) as a yellow oil(yield: 7.5%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.84(4H, m), 2.17(2H, m), 2.61(2H, m), 2.80(2H, m), 3.04(2H, t,J=8.4 Hz), 3.14(2H, m), 3.49(1H, m), 3.51(2H, t, J=8.4 Hz), 6.87(1H, t,J=1.6 Hz), 6.93(1H, dd, J=1.6, 7.2 Hz), 6.98(2H, m), 7.10(1H, d, J=7.2Hz), 7.16(2H, m), 7.43(1H, ddd, J=0.8, 4.8, 7.2 Hz), 8.10(1H, ddd,J=1.6, 2.0, 7.2 Hz), 8.78(1H, dd, J=0.8, 4.8 Hz), 8.97(1H, dd, J=0.8,2.0 Hz).

ESI-Mass: 430.2(MH+).

Next, oxalic acid (2 mg) was added to the above product to give theoxalate of the title compound.

m.p. (oxalate): 115° C.

Example 184: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-3-yl)-methyl]indoline

2-Methoxypyridine (0.3 ml) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.5 g) weretreated in accordance with the method described in J. Org. Chem., 1367(1988). to give the title compound (0.493 g) as a pale yellow oil(yield: 75.2%).

Next, oxalic acid was added thereto to give the oxalate of the titlecompound as an amorphous solid.

m.p. (oxalate): 101° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.82(4H, m), 2.81(2H, t, J=8.4 Hz), 2.96(4H, m), 3.14(2H, m),3.31(2H, t, J=8.4 Hz), 3.53(2H, m), 3.67(1H, m), 3.84(3H, s), 5.75(1H,s), 6.49(1H, dd, J=0.8, 7.4 Hz), 6.55(1H, d, J=0.8 Hz), 6.91(1H, d,J=7.4 Hz), 6.98(1H, dd, J=5.2, 7.6 Hz), 7.16(2H, m), 7.33(2H, m),7.79(1H, dd, J=2.0, 7.6 Hz), 8.02(1H, dd, J=2.0, 5.2 Hz).

ESI-Mass: 462.3(MH+).

Example 185: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-(2-methoxypyridin-3-yl)methyl]indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-3-yl)methyl]indoline(0.418 g) was treated as in Example 175 to give the title compound(0.040 g) as a pale yellow oil (yield: 9.9%).

Next, oxalic acid (8 mg) was added thereto to give the oxalate of thetitle compound as an amorphous solid.

m.p. (oxalate): 182° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.85(4H, m), 2.83(2H, t, J=8.4 Hz), 2.96(4H, m), 3.17(2H, m),3.31(2H, t, J=8.4 Hz), 3.54(2H, m), 3.65(1H, m), 3.75(2H, s), 3.87(3H,s), 6.39(1H, d, J=7.6 Hz), 6.41(1H, s), 6.90(1H, dd, J=5.2, 7.6 Hz),6.92(1H, d, J=7.6 Hz), 7.18(2H, m), 7.33(2H, m), 7.39(1H, dd, J=2.0, 7.6Hz), 8.01(1H, dd, J=2.0, 5.2 Hz).

ESI-Mass: 446.3(MH+).

Example 186: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-6-yl)-methyl]indoline

Tetramethylethylenediamine (0.26 ml) was added to6-bromo-2-methoxypyridine (0.32 g) synthesized in accordance with themethod described in Tetrahedron, 1373 (1985). and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.4 g) anddiethyl ether was employed as the solvent. The resultant mixture wastreated as in Example 93 to give the title compound (0.401 g) ascolorless crystals (yield: 76.5%).

Next, oxalic acid was added thereto to give the oxalate of the titlecompound as an amorphous solid.

m.p. (oxalate): 95° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.84(2H, m), 2.16(2H, m), 2.82(2H, t, J=8.4 Hz), 2.99(4H, m),3.16(2H, t), 3.30(2H, t, J=8.4 Hz), 3.54(2H, m), 3.68(1H, m), 3.81(3H,s), 5.48(1H, s), 6.52(3H, m), 6.92(1H, d, J=7.9 Hz), 7.09(1H, d, J=7.1Hz), 7.16(3H, m), 7.34(2H, m), 7.65(1H, d, J=7.6 Hz).

FAB-Mass: 462(MH+).

Example 187: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-1-6-[1-(2-methoxypyridin-6-yl)methyl]indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-6-yl)methyl]indoline(0.363 g) was treated as in Example 175 to give the title compound(0.127 g) as a pale yellow oil (yield: 39.2%).

Next, oxalic acid (26 mg) was added thereto to give the oxalate of thetitle compound as an amorphous solid.

m.p. (oxalate): 139° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83(4H, m), 2.84(2H, t, J=8.4 Hz), 2.87(2H, m), 2.93(2H, m),3.06(2H, m), 3.31(2H, t, J=8.4 Hz), 3.45(2H, m), 3.64(1H, m), 3.83(3H,s), 3.85(2H, s), 6.47(2H, m), 6.60(1H, d, J=8.2 Hz), 6.75(1H, d, J=7.3Hz), 6.93(1H, d, J=8.0 Hz), 7.16(2H, m), 7.32(2H, m), 7.57(1H, dd,J=7.3, 8.2 Hz).

FAB-Mass: 446(MH+).

Example 188: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-1-hydroxy-1-(2-methoxypyridin-5-yl)-methyl]indoline

A mixture of 5-bromo-2-methoxypyridine (0.32 g) synthesized inaccordance with the method described in Tetrahedron, 1373 (1985). and1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (0.4 g) anddiethyl ether employed as a solvent was treated as in Example 93 to givethe title compound (0.461 g) as a pale yellow oil (yield: 88.0%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.79(4H, m), 2.13(2H, m), 2.48(1H, br-d), 2.60(2H, m), 2.80(2H,m), 2.92(2H, t, J=8.4 Hz), 3.11(2H, br-d), 3.38(1H, m), 3.41(2H, t,J=8.4 Hz), 3.91(1H, ddd, J=0.4, 0.4, 2.8 Hz), 5.72(1H, d, J=2.4 Hz),6.42(1H, d, J=0.8 Hz), 6.55(1H, dd, J=0.8 Hz), 6.68(1H, dd, J=0.4, 8.8Hz), 6.97(3H, m), 7.15(2H, m), 7.56(1H, ddd, J=0.4, 2.4, 8.8 Hz),8.17(1H, ddd, J=0.4, 0.4, 2.4 Hz).

ESI-Mass: 462.2(MH+).

Next, oxalic acid or hydrochloric acid was added thereto to give theoxalate or the hydrochloride as a hygroscopic amorphous solid of thetitle compound.

Oxalate

M.p. (oxalate): 108° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.76(4H, m), 2.63(4H, m), 2.86(2H, t, J=8.2 Hz), 3.89(4H, m),3.31(2H, t, J=8.2 Hz), 3.33(2H, m), 3.55(1H, m), 3.80(3H, s), 5.58(1H,s), 6.54(1H, s), 6.72(1H, d, J=8.6 Hz), 6.92(1H, d, J=7.6 Hz), 7.14(2H,t, J=8.2 Hz), 7.30(2H, dd, J=5.6, 8.2 Hz), 7.57(1H, dd, J=2.2, 8.6 Hz),8.13(1H, d, J=2.2 Hz).

Oxalate

FAB-Mass: 462(MH+).

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.86(2H, m), 2.10(2H, m), 2.86(2H, t, J=8.4 Hz), 3.11(4H, m),3.24(2H, m), 3.34(2H, t, J=8.4 Hz), 3.64(2H, m), 3.75(1H, m), 3.82(3H,s), 5.61(1H, s), 6.55(1H, s), 6.58(1H, d, J=7.6 Hz), 6.67(1H, br-s),6.78(1H, d, J=8.4 Hz), 6.97(1H, d, J=7.6 Hz), 7.19(2H, m), 7.34(2H, m),7.63(1H, dd, J=2.4, 8.4 Hz), 8.16(1H, d, J=2.4 Hz).

FAB-Mass: 462(MH+).

Example 189: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-(2-methoxypyridin-5-yl)methyl]indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-5-yl)methyl]indoline(0.335 g) was treated as in Example 175 to give the title compound(0.046 g) as a pale yellow oil (yield: 14.2%).

Next, oxalic acid (10 mg) was added thereto to give the oxalate of thetitle compound.

m.p. (oxalate): 166° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.57(4H, m), 1.85(2H, m), 2.30(2H, m), 2.80(2H, m), 2.93(2H, t,J=8.4 Hz), 3.21(2H, m), 3.42(2H, t, J=8.4 Hz), 3.46(1H, m), 4.0(3H, s),4.89(1H, d, J=4.2 Hz), 5.59(1H, d, J=4.2 Hz), 6.45(1H, d, J=1.1 Hz),6.60(1H, d, J=7.3 Hz), 6.62(1H, d, J=8.2 Hz), 6.71(1H, d, J=7.3 Hz),6.99(2H, m), 7.00(1H, d, J=7.3 Hz), 7.18(2H, m), 7.50(1H, dd, J=7.3, 8.2Hz).

FAB-Mass: 446(MH+).

Example 190: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridon-5-yl)methyl]-indoline

The hydrochloride (0.101 g) of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-5-yl)methyl]indolinewhich had been prepared about one month before was allowed to stand atroom temperature for 2 months. Then, it was dissolved in ethyl acetateand mixed with a saturated aqueous solution of sodium bicarbonate andthe layers were separated. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. Next, the residue was purified by NH-silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(0.033 g) as pale yellow crystals.

m.p. (free): 202° C.

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.82(4H, m), 2.31(2H, m),2.68(2H,m), 2.86(2H, m), 2.92(2H, t,J=8.4 Hz), 3.19(2H, m), 3.38(1H, m), 3.42(2H, t, J=8.4 Hz), 5.53(1H, s),6.38(1H, br-s), 6.47(1H, d, J=932 Hz), 6.54(1H, dd, J=0.8, 7.2 Hz),6.95-7.01(3H, m), 7.14-7.17(2H, m), 7.32(1H, d, J=2.4 Hz), 7.44(1H, dd,J=2.4, 9.2 Hz).

FAB-Mass: 448(MH+).

Example 191-1: Synthesis of 5-bromo-2-dimethylaminopyridine

2-Dimethylaminopyridine (1.0 ml) was dissolved in chloroform (60 ml).After adding tributylammonium bromide (3.88 g) thereto, the resultantmixture was stirred for 7 min. Then the reaction solution was washedwith an aqueous solution of sodium thiosulfate and water, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate-methanol system) to give the title compound (1.097 g) as yellowcrystals (yield: 72.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.05(6H, s), 6.40(1H, dd, J=0.8, 8.8 Hz), 7.48(1H, dd, J=2.8, 8.8Hz), 8.16(1H, dd, J=0.8, 2.8 Hz).Example 191-2: Synthesis of 2-dimethylamino-5-formylpyridine

Tetramethylethylenediamine (8.0 ml) was added to the mixture of5-bromo-2-dimethylaminopyridine (5.0 g), N,N-dimethylformamide (6.1 ml)and diethyl ether employed as the solvent. The resultant mixture wastreated in as in Example 93 to give the title compound (3.273 g) as paleyellow crystals (yield: 89.6%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.21(6H, s), 6.56(1H, dd, J=0.4, 9.2 Hz), 7.91(1H, dd, J=2.4, 9.2Hz), 8.55(1H, dd, J=0.4, 2.4 Hz), 9.77(1H, s).Example 191-3: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-hydroxy-1-(2-dimethylaminopyridin-5-yl)methyl]indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.5 g) and2-dimethylamino-5-formylpyridine (0.345 g) were treated as in Example130 to give the title compound (0.376 g) as a colorless oil (yield:65.3%).

Next, hydrochloric acid was added thereto to give the hydrochloride ofthe title compound as an amorphous solid.

m.p. (hydrochloride): 185-196° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.86(2H, m), 2.08-2.18(2H, m), 2.86(2H, t, J=8.4 Hz),3.07-3.15(4H, m), 3.21(6H, s), 3.71(2H, m), 3.34(2H, t, J=8.4 Hz),3.64(2H, br-d), 3.73(1H, m), 5.63(1H, s), 6.56(1H, d, J=7.4 Hz),6.69(1H, s), 6.98(1H, t, J=7.4 Hz), 7.18(3H, m), 7.34(2H, m), 7.85(1H,dd, J=2.0, 9.6 Hz), 7.90(1H, d, J=2.0 Hz).

ESI-Mass: 475.2(MH+).

Example 192-1: Synthesis of 5-bromo-2-chloropyridine

5-Bromo-2-methoxypyridine (1.88 g) was treated in accordance with themethod described in Synth. Commun., 2971 (1990). to give the titlecompound (0.046 g) as a pale yellow oil (yield: 14.2%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 7.24(1H, dd, J=0.4, 8.1 Hz), 7.77(1H, dd, J=2.4, 8.1 Hz),8.47(1H, dd, J=0.4, 2.4 Hz).Example 192-2: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1hydroxy-1-(2-chloropyridin-5-yl)-methyl]indoline

5-Bromo-2-chloropyridine (0.151 g) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.2 g) weretreated as in Example 93 to give the title compound (0.130 g) as acolorless oil (yield: 49.7%).

Next, hydrochloric acid was added thereto to give the hydrochloride ofthe title compound as an amorphous solid.

m.p. (hydrochloride): 136° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.84(2H, m), 2.12(2H, m), 2.84(2H, t, J=8.4 Hz), 3.04-3.17(4H,m), 3.16(2H, t, J=8.4 Hz), 3.65(2H, br-d), 3.74(1H, m), 5.68(1H, s),6.58(1H, d, J=7.6 Hz), 6.64(1H, s), 6.97(1H, d, J=7.6 Hz), 7.19(2H, m),7.34(2H, m), 7.43(1H, d, J=8.4 Hz), 7.76(1H, dd, J=2.4, 8.4 Hz),8.42(1H, d, J=2.4 Hz).

ESI-Mass: 466.1(MH+).

Example 193: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-(2-thiazolyl)-1-hydroxymethyl]indoline

Thiazole (0.12 ml) was dissolved in tetrahydrofuran (5 ml). In anitrogen atmosphere at −78° C., a 1.66 M solution (1.0 ml) ofn-butyllithium in n-hexane was added dropwise into the solution obtainedabove and the resultant mixture was stirred under the same conditionsfor 10 min. Next,1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.5 g)dissolved in tetrahydrofuran (7 ml) was added thereto and the resultantmixture was stirred at −78° C. for 3 hr. To the reaction solution weresuccessively added a saturated aqueous solution of ammonium chloride andethyl acetate (200 ml) and the layers were separated. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby NH-silica gel column chromatography (hexane/ethyl acetate/methanolsystem) to give the title compound (0.134 g) as a pale yellow oil(yield: 32.6%).

Next, oxalic acid (3 mg) was added to 40 mg of the above product to givethe oxalate of the title compound as a colorless amorphous solid.

m.p. (oxalate): 118° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.78(4H, m), 2.84(2H, t, J=8.6 Hz), 2.89(4H, m), 2.95(2H, m),3.32(2H, t, J=8.6 Hz), 3.37(2H, m), 3.58(1H, m), 4.81(1H, s), 5.56(1H,s), 6.00(1H, d, J=7.2 Hz), 6.95(1H, d, J=7.2 Hz), 7.15(2H, m), 7.31(2H,m), 7.59(1H, d, J=3.0 Hz), 7.66(1H, d, J=3.0 Hz).

ESI-Mass: 438.2(MH+).

Example 194: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(2-thiazolylcarbonyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-(2-thiazolyl)-1-hydroxymethyl]indoline(0.1 g) was treated in accordance with the method described in J. Org.Chem., 2480 (1978). to give the title compound (0.022 g) as a yellow oil(yield: 22.1%).

Next, oxalic acid (5 mg) was added thereto to give the oxalate of thetitle compound as a colorless amorphous solid.

m.p. (oxalate): 132° C.

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.51(4H, m), 1.82(2H, m), 2.62(2H, m), 2.80(2H, m), 2.97(2H, t,J=8.4 Hz), 3.14(2H, m), 3.43(2H, t, J=8.4 Hz), 3.49(1H, m), 6.20(2H, m),7.11(3H, m), 7.17(1H, br-s), 7.61(1H, d, J=3.2 Hz), 7.89(1H, d, J=7.6Hz), 7.99(1H, d, J=3.2 Hz).

FAB-Mass: 436(MH+).

Example 195-Synthesis of1-1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-(4-thiazolyl)-1-hydroxymethyl]indoline

4-Bromo-2-trimethylsilylthiazole (0.2 g) synthesized in accordance withthe method described in J. Org. Chem., 1749 (1988). and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.2 g) weretreated as in Example 193 to give the title compound (0.039 g) as apaleyellow oil (yield: 15.7%).

Next, oxalic acid (4 mg) was added thereto to give the oxalate of thetitle compound as an amorphous solid.

m.p. (oxalate): 115° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.78(4H, m), 2.74(2H, m), 2.83(2H, t, J=8.4 Hz), 2.89(2H, m),2.97(2H, m), 3.31(2H, t, J=8.4 Hz), 3.38(2H, m), 3.57(1H, m), 5.72(1H,s), 6.55(2H, m), 6.92(1H, d, J=7.2 Hz), 7.15(2H, m), 7.31(2H, m),7.44(1H, dd, J=0.4, 2.0 Hz), 8.96(1H, d, J=2.0 Hz).

FAB-Mass: 438(MH+).

Example 196; Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-(5-thiazolyl)-1-hydroxymethyl]indoline

2-Trimethylsilylthiazole (0.134 g) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.2 g) weretreated as in Example 193 to give the title compound (0.145 g) as a paleyellow oil (yield: 58.4%).

Next, oxalic acid (15 mg) was added thereto to give the oxalate of thetitle compound as an amorphous solid.

m.p. (oxalate): 112° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80(4H, m), 2.86(2H, t, J=8.4 Hz), 2.91(4H, m), 3.04(2H, m),3.33(2H, t, J=8.4 Hz), 3.46(2H, m), 3.62(1H, m), 5.90(1H, s), 6.58(2H,m), 6.97(1H, d, J=7.2 Hz), 7.16(2H, m), 7.31(2H, m), 7.66(1H, s),8.93(1H, s).

FAB-Mass: 438(MH+).

Example 197: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-[1-hydroxy-1-(pyrimidin-2-yl)methyl]-indoline

2-Tributylstannylpyridine (0.2 g) synthesized in accordance with themethod described in J. Am. Chem. Soc. 1481 (1978). and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.21 g) weretreated in accordance with the method described in Tetrahedron Lett.,275 (1994). to give the title compound (0.038 g) as a yellow oil (yield:16.2%).

Next, oxalic acid (8 mg) was added thereto to give the oxalate of thetitle compound as an amorphous solid.

m.p. (oxalate): 123° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.84(4H, m), 2.82(2H, t, J=8.2 Hz), 2.98(2H, m), 3.04(2H, m),3.19(2H, m), 3.29(2H, t, J=8.2 Hz), 3.58(2H, m), 3.68(1H, m), 5.65(1H,s), 6.60(1H, d, J=7.2 Hz), 6.65(1H, s), 6.91(1H, d, J=7.2 Hz), 7.18(2H,m), 7.33(2H, m), 7.36(1H, t, J=4.8 Hz), 8.76(2H, d, J=4.8 Hz).

ESI-Mass: 433.3(MH+).

Fxample 198: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-[1-hydroxy-1-(pyrimidin-5-yl)methyl]-indoline

5-Bromopyridine (1.27 g) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.21 g) weretreated in accordance with the method described in Synth. Commun., 253(1994). to give the title compound (0.624 g) as a pale yellow oil(yield: 36.1%).

Next, oxalic acid (32 mg) was added to 0.156 g of the above product togive the oxalate of the title compound as a hygroscopic amorphous solid.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.78-1.92(4H, m), 2.84(2H, t, J=8.4 Hz), 2.95(4H, m), 3.13(2H,m), 3.23(2H, t, J=8.2 Hz), 3.51(2H, m), 3.68(1H, m), 5.71(1H, s),6.59(1H, d, J=7.0 Hz), 6.60(1H, s), 6.97(1H, d, J=7.0 Hz), 7.17(2H, m),7.33(2H, m), 8.75(2H, s), 9.04(1H, s).

FAB-Mass: 433(MH+).

Example 199: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-[1-hydroxy-1-(2-pyrrolyl)methyl]indoline

1-[l-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.2 g) and2-pyrrolecarboxyaldehyde (0.44 ml) were treated as in Example 193 togive the title compound (0.044 g) as a colorless oil (yield: 21.0%).

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.80(4H, m), 2.14(2H, m), 2.60(2H, m), 2.81(2H, m), 2.94(2H, t,J=8.4 Hz), 3.12(2H, br-d), 3.38(1H, m), 3.42(2H, t, J=8.4 Hz), 5.79(1H,s), 6.03(1H, m), 6.13(1H, m), 6.50(1H, d, J=1.2 Hz), 6.62 (1H, dd,J=1.2, 7.2 Hz), 6.71(1H, m), 6.97 (2H, m), 7.02(1H, d, J=7.2 Hz),7.15(2H, m), 8.33(1H, m).

Fab-Mass: 420(MH+).

Example 200: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-N,N-dimethylaminomethylindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (500 mg),formaldehyde (290 mg) and formic acid (180 mg) were treated as inExample 170 to give the hydrochloride (60 mg) of the title compound as apale brown hygroscopic amorphous solid (yield: 9.3%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.94-2.03(2H, m), 2.04-2.17(2H, m), 2.66(3H, s), 2.67(3H, s),2.92(2H, t, J=8 Hz), 3.00-3.12(4H, m), 3.26-3.35(2H, m), 3.39(2H, t, J=8Hz), 3.58-3.70(3H, m), 4.12(2H, s), 6.65(1H, d, J=8 Hz), 6.93(1H, s),7.08(1H, d, J=8 Hz), 7.16-7.21(2H, m), 7.32-7.36(2H, m), 10.52(1H,br-s), 10.62(1H, br-s).

FAB-Mass: 382(MH+).

Example 201-1: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-bromoindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.1 g) wasdissolved in chloroform (27 ml). After adding manganese dioxide (2.75g), the resultant mixture was heated under reflux for 4 hr. Thenmanganese dioxide was filtered off and the filtrate was concentratedunder reduced pressure to give the title compound (0.480 g) as a yellowoil (yield: 96.5%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 2.09(4H, m) 2.25(2H, m), 2.50(2H, m), 2.82(2H, m) 3.17 (2H,br-d), 4.17 (1H, m), 6.49(1H, d, J=2.8 Hz), 6.99(2H, m) 7.18(2H, m),7.20(1H, d, J=8.4 Hz), 7.21(1H, d, J=2.8 Hz), 7.48(1H, d, J=8.4 Hz),7.53(1H, br-s).Example 201-2: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(4-fluorophenyl)indole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindole (0.1 g),4-fluorophenylboronic acid (0.067 g), tetraquistripehnylphosphinepalladium (0.014 g) and sodium carbonate (0.12 g) were dissolved intoluene (5 ml) and water (1.2 ml) and the resultant solution was stirredat 90° C. for 12 hr. After filtering the reaction mixture, ethyl acetateand a saturated aqueous solution of sodium bicarbonate were added to thefiltrate and the layers were separated. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. Then the residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate system) to give the titlecompound (0.075 g) as pale yellow crystals (yield: 71.6%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 2.19(4H, m), 2.42(2H, m), 2.75(2H, m), 2.89(2H, m) 3.27(2H, m),4.33(1H, m), 6.51(1H, d, J=2.4 Hz), 6.98(2H, m), 7.14(6H, m), 7.30(1H,dd, J=1.4, 8.0 Hz), 7.44(1H, s), 7.59(2H, m), 7.67(1H, d, J=8.0 Hz)Example201-3: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(4-fluorophenyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(4-fluorophenyl)indole (0.075g) was treated as in Production Example 56-2 to give the title compound(0.020 g) as a yellow oil (yield: 26.6%).

Next, oxalic acid was added thereto to give the oxalate of the titlecompound.

m.p. (oxalate): 130-145° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆)

δ(ppm) 1.93(2H, m), 2.08(2H, m), 2.93(2H, t, J=8.2 Hz), 3.10(4H, m),3.25(2H, m), 3.39(2H, t, J=8.2 Hz), 3.64(2H, m), 3.89(1H, m), 6.77(1H,s), 6.82(1H, d, J=7.4 Hz), 7.00(1H, d, J=7.4 Hz) 7.19 (2H, m), 7.25(2H,m), 7.34 (2H, m), 7.65 (2H, m)

FAB-Mass: 417(MH+).

Example 202: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(2-pyrrolidon-1-yl)methylindoline

60% Sodium hydride (40 mg) was added to a solution of 2-pyrrolidone (85mg) in dimethylformamide (10 ml) and the resultant mixture was stirredat 50° C. for 2 hr. Next,1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (200 mg)was added thereto and the resultant mixture was stirred for additional 2hr. Then ethyl acetate and water were added to the reaction solution andthe layers were separated. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/ethanol system) followed by conversion into ahydrochloride in a conventional manner to give the hydrochloride (170mg) of the title compound as a purple powder (yield: 69%).

m.p. (hydrochloride): 140-142° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.92(4H, m), 1.94-2.08(2H, m), 2.25(2H, t, J=8 Hz),2.81-2.87(2H, m), 3.00-3.35(10H, m), 3.57-3.74(3H, m) 4.22(2H, s)6.35(1H, s), 6.40(1H, d, J=8 Hz),6.96(1H, d, J=8 Hz) 7.14-7.19(2H, m),7.30-7.34(2H, m).

FAB-Mass: 422(MH+).

Example 203: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(2-piperdin-1-yl)methylindoline

2-Piperidone (64 mg), 60% sodium hydride (26 mg) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (200 mg)were treated as in Example 202 to give the hydrochloride (130 mg) of thetitle compound as a dark red hygroscopic amorphous solid (yield: 51%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.60-1.73(4H, m), 1.82-1.89(2H, m), 2.02-2.15(2H, m),2.26-2.32(2H, m), 2.87(2H, t, J=8 Hz), 3.04-3.16(6H, m), 3.21-3.28(2H,m), 3.34(2H, t, J=8 Hz), 3.60-3.70(2H, m), 4.40(2H, s), 6.41(1H, s),6.45(1H, d, J=8 Hz), 6.98(1H, d, J=8 Hz), 7.16-7.21(2H, m),7.32-7.36(2H, m).

FAB-Mass: 4³6(MH+).

Example 204: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(succinimido-1-yl)methylindoline

Succinimide (64 mg), 60% sodium hydride (26 mg) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (200 mg)were treated as in Example 202 to give the hydrochloride (140 mg) of thetitle compound as a dark purple hygroscopic amorphous solid (yield:55%).

¹H-NMR (400 MHz, DMSO-d₆)

δ(ppm) 1.84-2.05(4H, m), 2.67(4H, s), 2.85(2H, t, J=8 Hz) 3.02-3.20(4H,m), 3.24-3.35(4H, m), 3.60-3.75(3H, m), 4.43(2H, s), 6.41-6.44(2H, m),6.94(1H, d, J=8 Hz), 7.17-7.22(2H, m), 7.32-7.37(2H, m).

FAB-Mass: 436(MH+).

Example 205: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(glutarimido-1-yl)methylindoline

Glutarimide (73 mg), 60% sodium hydride (26 mg) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (200 mg)were treated as in Example 202 to give the oxalate (240 mg) of the titlecompound as a pale brown powder (yield: 82%).

m.p. (oxalate): 109-111° C.

¹H-NMR (400 MHz, DMSO-d6):

δ(ppm) 1.80-1.91(6H, m), 2.65(4H, t, J=6 Hz), 2.83(2H, t, J=8 Hz),2.92-3.04(4H, m), 3.12-3.22(2H, m), 3.31(2H, t, J=8 Hz), 3.49-3.71(3H,m), 4.72(2H, s), 6.35-6.37(2H, m), 6.91(1H, d, J=8 Hz), 7.15-7.20(2H,m), 7.31-7.35(2H, m).

FAB-Mass: 450(MH+).

Example 206: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(2-imidazolidonyl)methylindoline

2-Imidazolidone (60 mg), 60% sodium hydride (28 mg) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (260 mg)were treated as in Example 202 to give the oxalate (120 mg) of the titlecompound as white prisms (yield: 33%).

m.p. (oxalate): 184-186° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80-1.89 (4H, m),2.86 (2H, t, J=8 Hz) 2.90-2.99 (4H, m),3.08-3.24(6H, m), 3.33(2H, t, J=8 Hz), 3.47-3.55(2H, m), 3.60-3.68(1H,m), 4.10(2H, s), 6.34-6.37(2H, m), 6.43(1H, d, J=8 Hz), 6.97 (1H, d, J=8Hz), 7.15-7.19 (2H, m),7.31-7.34 (2H, m)

FAB-Mass: 423(MH+).

Example 207: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(2,4-imidazolidinedion-3-yl)methylindoline

Hydantoin (130 mg), 60% sodium hydride (54 mg) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (400 mg)were treated as in Example 202 to give the title compound (230 mg) as awhite powder (yield: 49%).

m.p.: 191-193° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.68-1.84 (4H, m), 2.11-2.21(2H, m) 2.56-2.63(2H, m),2.76-2.83(2H, m), 2.90(2H, t, J=8 Hz), 3.06-3.15(2H, m), 3.39(2H, t, J=8Hz), 3.35-3.46(1H, m), 3.92(2H, s), 4.57(2H, s), 5.90 (1H, s), 6.47 (1H,s), 6.65 (1H, d, J=8 Hz), 6.94-7.00(3H, m), 7.13-7.19(2H, m)

FAB-Mass: 436(MH+).

Example 208: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(2-oxazolidon-3-yl)methylindoline

2-Oxazolidone (120 mg), 60% sodium hydride (54 mg) and1-[l-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (400 mg)were treated as in Example 202 to give the hydrochloride (450 mg) of thetitle compound as a pale red hygroscopic amorphous solid (yield: 92%).

¹H-NMR (400 MHz, DMSO-d₆)

δ(ppm) 1.82-1.90(2H, m), 2.05-2.18(2H, m), 2.89(2H, t, J=8 Hz),3.03-3.15(4H, m), 3.19-3.28(2H, m), 3.31-3.80(7H, m) 4.21-4.29(4H, m),6.44-6.50(2H, m), 7.01(1H, d, J=8 Hz), 7.16-7.21(2H, m), 7.32-7.36(2H,m).

FAB-Mass: 424(MH+).

Example 209: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(2,4-thiazolidinedion-3-yl)methylindoline

2,4-Thiazolidinedione (110 mg), 60% sodium hydride (40 mg) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (300 mg)were treated as in Example 202 to give the hydrochloride (120 mg) of thetitle compound as a red hygroscopic amorphous solid (yield: 30%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-2.06(4H, m), 2.86(2H, t, J=8 Hz), 3.10-3.19(4H, m),3.24-3.35(4H, m), 3.60-3.76(3H, m), 4.27(2H, s), 4.56(2H, s),6.43-6.45(2H, m), 6.97(1H, d, J=8 Hz), 7.17-7.22(2H, m) 7.32-7.36(2H, m)

FAB-Mass: 454(MH+).

Example 210: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(pyrrol-1-yl)methylindoline

Pyrrole (50 mg), 60% sodium hydride (30 mg) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (250 mg)were treated as in Example 202 to give the hydrochloride (240 mg) of thetitle compound as a brown powder (yield: 82%).

m.p. (hydrochloride): 162° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d):

δ(ppm) 1.80-1.87 (2H m), 2.06-2.19(2H, m), 2.84(2H, t, J=8 Hz),2.99-3.12 (4H, m), 3.18-3.25(2H, m), 3.33 (2H, t, J=8 Hz), 3.56-3.70(3H,m), 4.92(2H, s), 5.94-5.96(2H, m), 6.41(1H, d, J=8 Hz), 6.52(1H, s),6.75-6.77 (2H, m), 6.95(1H, d, J=8 Hz) 7.14-7.19(2H, m), 7.29-7.34(2H,m), 11.06(1H, br-s).

FAB-Mass: 405(MH+).

Example 211: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(imidazol-1-yl)methylindoline

Imidazole (50 mg), 60% sodium hydride (30 mg) and1-[1-(4-fluorophenethylpiperidin-4-yl]-6-chloromethylindoline (250 mg)were treated as in Example 202 to give the hydrochloride (260 mg) of thetitle compound as a red hygroscopic amorphous solid (yield: 88%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90(2H, m), 2.15-2.28(2H, m), 2.86(2H, t, J=8 Hz),2.99-3.14 (4H, m), 3.21-3.29 (2H, m), 3. 36 (2H, t, J=8 Hz) 3.58-3.68(3H, m), 5.25 (2H, s), 6.59 (1H, d, J=8 Hz), 6. 81 (1H, s), 7.01 (1H, d,J=8 Hz), 7.14-7.19 (2H, m), 7.30-7.34 (2H, m),7.66(1H, s), 7.82 (1H, s),11.07 (1H, br-s)

FAB-Mass: 405(MH+).

Example 212: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(1,2,3-triazol-1-yl)methylindolineand1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-(1,2,3-triazol-2-yl)methylindoline

1,2,3-Triazole (51 mg), 60% sodium hydride (30 mg) and1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethyl-indoline (250 mg)were treated as in Example 202 to give the hydrochloride (180 mg) ofhighly polar1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2,3-triazol-1-yl)methylindolineas a dark red hygroscopic amorphous solid (yield: 61%), and also thehydrochloride (40 mg) of lowly polar1-[1-(4-fluorophenethyl)piperidin-4yl]-6-(1,2,3-triazol-2-yl)methylindolineas a pale red hygroscopic amorphous solid (yield: 14%).

(1)1-[1-(4-Fluorophenethyl)piperdin-4-yl)-6-(1,2,3-triazol-1-yl)methylindoline(highly polar)

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80-1.88(2H, m), 2.05-2.18(2H, m), 2.87(2H, t, J=8 Hz),3.02-3.14(4H, m), 3.21-3.30(2H, m),3.34(2H, t, J=8 Hz) 3.60-3.75(3H, m),5.46(2H, s), 6.51(1H, d, J=8 Hz), 6.57(1H, s), 7.00(1H, d, J=8Hz),7.16-7.21(2H, m),7.32-7.40(2H, m),7.73(1H, s), 8.17(1H, S),10.88(1H, br-s).

FAB-Mass: 406(MH+).

(2)1-1[-(4-Fluorophenethyl)piperdin-4-yl]-6-(1,2,3-triazol-2-yl)methylindoline(lowly polar)

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90(2H, m), 1.94-2.10(2H, m), 2.86(2H, t, J=8 Hz),3.01-3.18(4H, m),3.22-3.30(2H, m),3.33(2H, t, J=8 Hz) 3.60-3.75(3H, m),5.49(2H, s), 6.45(1H, d, J=8 Hz), 6.48(1H, s) 6.98(1H, d, J=8 Hz),7.17-7.22(2H, m), 7.32-7.36(2H, m), 7.78(2H, s).

FAB-Mass: 406(MH+)

Example 213: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(1,2,4-triazol-2-yl)methylindoline

1,2,4-Triazole (51 mg), 60% sodium hydride (30 mg) and1-[1-(4-fluorophenethylpiperidin-4-yl]-6-chloromethylindoline (250 mg)were treated as in Example 202 to give the hydrochloride (210 mg) of thetitle compound as a brown hygroscopic amorphous substance (yield: 71%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90 (2H, m), 1.95-2.14 (2H, m), 2.87 (2H, t, J=8 Hz),3.01-3.15(4H, m), 3.21-3.32(2H, m), 3.34(2H, t, J=8 Hz) 3.60-3.74 (3H,m), 5.27 (2H, s),6.48 (1H, d, J=8 Hz),6.50-6.59 (1H, m), 6.99(1H, d, J=8Hz), 7.17-7.22(2H, m), 7.32-7.40(2H, m) 7.97-8.00(1H, m), 8.64-8.72(1H,m).

FAB-Mass: 406(MH+).

Example 214: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-(2-tiazolyl)methylindoline

A mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-thiocarbamoylmethylindoline(150 mg), 40% chloroacetaldehyde (300 mg), potassium carbonate (79 mg)and dimethoxyethane (32 ml) was stirred overnight. Then the liquidreaction mixture was filtered and the filtrate was concentrated underreduced pressure. To the residue were added trifluoroacetic anhydride(240 mg), pyridine (210 mg) and dimethoxyethane (4 ml) and the resultantmixture was stirred for 30 min. Then the reaction solution wasconcentrated under reduced pressure and diluted with a saturated aqueoussolution of sodium bicarbonate and ethyl acetate. The organic layer waswashed with a saturated aqueous solution of sodium chloride and driedover anhydrous magnesium sulfate. The residue was purified by NH-silicagel column chromatography (hexane/ethyl acetate system) followed byconversion into a hydrochloride in a conventional manner to give thehydrochloride (40 mg) of the title compound as a brown hygroscopicamorphous solid (yield: 23%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.82-1.90(2H, m), 2.03-2.15(2H, m), 2.88(2H, t, J=8 Hz),3.03-3.15(4H, m), 3.20-3.28(2H, m), 3.35(2H, t, J=8 Hz), 3.58-3.66(2H,m), 3.68-3.80(1H, m), 4.23(2H, s), 6.55(1H, d, J=8 Hz), 6.57 (1H, s),6.99 (1H, d, J=8 Hz), 7.16-7.21 (2H, m), 7.31-7.35 (2H, m), 7.60 (1H,s), 7.75 (1H, s) 10.82 (1H, br-s).

FAB-Mass: 422(MH+).

Example 215: Syntesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-3-(4-methoxybenzyl)indoline

3-(4-Methoxybenzyl)indoline (0.2 g) and1-(4-fluorophenethyl)-4-piperidone (0.262 g) were treated as in Example16 to give the title compound (0.343 g) as a colorless oil (yield:94.9%).

Next, oxalic acid (36 mg) was added thereto to give the oxalate (0.101g) of the title compound as colorless crystals.

m.p. (oxalate): 187° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80(4H, m), 2.63(1H, dd, J=9.0, 13.6 Hz), 2.96(4H, m), 3.15 (4H,m), 3.27 (1H, t, J=8.6 Hz), 3.43 (1H, m), 3.52 (2H, m), 3.67(1H, m),3.74(3H, s), 6.52(1H, d, J=7.6 Hz), 6.55(1H, t, J=7.6 Hz), 6.87 (2H, d,J=8.4 Hz), 6.92 (1H, d, J=7.6 Hz) 7.01(1H, t, J=7.6 Hz), 7.16(2H, d,J=8.4 Hz), 7.18(2H, d, J=8.4 Hz), 7.32(2H, dd, J=6.0, 8.4 Hz).

ESI-Mass: 445.3(MH+).

Example 216: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-3-methylindoline

3-Methylindoline (0.2 g) and 1-(4-fluorophenethyl)-4-piperidone (0.50 g)were treated as in Example 16 to give the title compound (0.384 g) as apale yellow oil (yield: 7.0.7%) Next, hydrochloric acid was addedthereto to give a salt followed by recrystallization from ethanol. Thusthe hydrochloride (0.314 g) of the title compound was obtained ascolorless crystals.

m.p. (hydrochloride): 232° C.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.25(3H, d, J=6.8 Hz), 1.89(2H, m), 2.33(2H, m), 2.88(1H, t,J=8.0 Hz), 3.10(4H, m), 3.23(3H, m), 3.55(1H, t, J=8.0 Hz), 3.61 (2H,m), 3.78 (1H, m), 6.67 (2H, m), 7.06 (2H, m) 7.18 (2H, t, J=8.8 Hz),7.33 (2H, m).

ESI-Mass: 339.2(MH+).

Example 217:1-[1-(4-fluorophenethyl)piperdin-4-yl]-5-chloro-6-aminoindoline

N-Chlorosuccinimide (0.24 g) was added at room temperature to a solutionof 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.5 g) inacetonitrile (50 ml) and the resultant mixture was stirred for 1 hr.Then the reaction mixture was filtered and concentrated under reducedpressure. Next, a 5 N aqueous solution of sodium hydroxide and ethylacetate were added thereto and the layers were separated. The organiclayer was washed with brine and dried over anhydrous magnesium sulfate.The resulting residue was purified by silica gel column chromatography(methylene chloride/ethanol system) to give the title compound (0.19 g)as a brown oil (yield: 34%).

¹H-NMR (400 MHz, CDCl₃)

δ(ppm) 1.69-1.83 (4H, m), 2.03-2.11 (2H, m), 2.51-2.60 (2H, m),2.75-2.82(2H, m), 2.83(2H, t, J=8 Hz), 3.08-3.15(2H, m), 3.20-3.32(1H,m), 3.38(2H, t, J=8 Hz), 3.85(2H, br-s), 5.89(1H, s), 6.89(1H, s),6.92-7.00(2H, m), 7.11-7.21(2H, m).Example 218: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4yl]-5-chloro-6-methanesulfonylaminoindoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-5-chloro-6-aminoindoline (0.19g) and methanesulfonyl chloride (0.058 g) were treated as in Example 116to give the oxalate (160 mg) of the title compound as a pale red powder(yield: 58%).

m.p. (oxalate): 193-196° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.73-1.83(4H, m), 2.81-3.00(6H, m), 2.91(3H, s), 3.09-3.15(2H,m), 3.37(2H, t, J=8 Hz), 3.42-3.56(2H, m), 3.58-3.65(1H, m), 6.49(1H,s), 7.10(1H, s), 7.12-7.20(2H, m), 7.23-7.31(2H, m)

FAB-Mass: 452(MH+).

Example 219: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-5-chloro-6-methoxyindoline

N-Chlorosuccinimide (0.15 g) was added at room temperature to a solutionof 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline (0.39 g) inmethylene chloride (5 ml) and the resultant mixture was stirred for 20min. Then a 5 N aqueous solution of sodium hydroxide and ethyl acetatewere added to the reaction solution and the layers were separated. Theorganic layer was washed with brine and dried over anhydrous magnesiumsulfate. The resulting residue was purified by silica gel columnchromatography (methylene chloride/ethanol system) followed byconversion into a hydrochloride to give the hydrochloride (0.10 g) ofthe title compound as apale red powder (yield: 21%).

m.p. (hydrochloride) 135-138° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-2.08(4H, m),2.82(2H, t, J=8 Hz),3.00-3.12(4H, m),3.21-3.29(2H, m), 3.34(2H, t, J=8 Hz), 3.60-3.67(2H, m), 3.72-3.84(1H,m), 3.79(3H, s), 6.34(1H, s), 6.99(1H, s), 7.15-7.20(2H, m),7.30-7.34(2H, m).

FAB-Mass: 399(MH+).

Example 220: Synthesis of1-[1-(1-(2,4-diffluorophenethyl)-piperdin-4-yl]-6-aminodoline

1-(Piperidin-4-yl)-6-nitroindoline (3.5 g) was treated as in Example 2or Example 110 to give the title compound (2.4 g) as a pale yellowpowder (yield: 40%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.69-1.88(4H, m), 2.09-2.15(2H, m), 2.52-2.60(2H, m),2.78-2.89(2H, m), 3.07-3.11(2H, m), 3.14-3.21(1H, m), 3.22(2H, t, J=8Hz), 3.50(2H, br-s), 5.81(1H, s), 5.98(1H, d, J=8 Hz), 6.72-6.83(3H, m),7.10-7.20(1H, m).Example 221: Synthesis of1-[1-(2,4-difluorophenethyl)-piperdin-4-yl]-6-methanesulfonylaminoindoline

1-[1-(2,4-Difluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.4 g) andmethanesulfonyl chloride (0.51 g) were treated as in Example 116 to givethe hydrochloride (240 mg) of the title compound as a pale yellowhygroscopic amorphous solid (yield: 45%).

¹H-NMR (400 MHz, DMSO-d6):

δ(ppm) 1.83-1.89(2H, m), 1.99-2.10(2H, m), 2.84(2H, t, J=8 Hz), 2.89(3H,s), 3.05-3.27(6H, m), 3.33(2H, t, J=8 Hz), 3.35-3.43(1H, m),3.59-3.68(2H, m), 6.38-6.41(2H, m), 6.94(1H, d, J=8 Hz), 7.06-7.11(1H,m), 7.22-7.28(1H, m), 7.39-7.45(1H, m), 9.34(1H, br-s), 10.76(1H, br-s).

FAB-Mass: 436(MH+)

Example 222: Synthesis of1-[1-(2,4-difluorophenethyl)-piperdin-4-yl]-6-acetamidoindoline

1-[1-(2,4-Difluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.6 g) andacetic anhydride (5 ml) were treated as in Example 133 to give thehydrochloride (640 mg) of the title compound as a white powder (yield:87%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-1.98 (4H, m), 1.99 (3H, s), 2.81 (2H, t, J=8 Hz) 3.00-3.13(4H, m), 3.22-3.33 (4H, m), 3.55-3.69 (3H, m), 6.58 (1H, d, J=8 Hz),6.90 (1H, d, J=8 Hz), 6.95 (1H, s), 7.07-7.12 (1H, m) 7.24-7.30(1H, m)7.39-7.45(1H, m), 9.69(1H, br-s).

FAB-Mass: 400(MH+).

Example 223: Synthesis of1-[1-(2,4-difluorophenethyl)-piperdin-4-yl]-6-bromoindoline

1-(Piperidin-4-yl)-6-bromoindoline (3.0 g) and 2,4-difluorophenethylbromide (3.1 g) were treated as in Example 2 to give the title compound(2.7 g) as a white powder (yield: 60%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.70-1.85(4H, m), 2.10-2.21(2H, m), 2.51-2.63(2H, m),2.79-2.89(2H, m), 2.90(2H, t, J=8 Hz), 3.08-3.17(2H, m), 3.28-3.37(1H,m), 3.41(2H, t, J=8 Hz), 6.48(1H, s), 6.69(1H, d, J=8 Hz), 6.72-6.84(2H,m), 6.90(1H, d, J=8 Hz), 7.11-7.20(1H, m)Example 224: Synthesis of1-[1-(2,4-difluorophenethyl)-piperdin-4-yl]-6-acetamidomethylindoline

1-[1-(2,4-Difluorophenethyl)piperidin-4-yl]-6-bromoindoline (3.5 g) wastreated as in Examples 130 to 133 to give the hydrochloride (0.26 g) ofthe title compound as a gray powder (yield: 7.3%).

m.p. (hydrochloride): 179° C. (decomp.)

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80(3H, s), 1.85-2.05(4H, m), 2.90(2H, t, J=8 Hz) 3.03-3.28(4H,m), 3.21-3.39(4H, m), 3.64-3.78(3H, m), 4.30(2H, s), 6.51-6.60(2H, m),6.98-7.08(2H, m), 7.11-7.19(1H, m), 7.32-7.40(1H, m), 8.25(1H, br-s).

FAB-Mass: 414(MH+).

Example 225: Synthesis of1-[1-(2,4-difluorophenethyl)-piperdin-4-yl]-6-carbamoylmethylindoline

1-[1-(2,4-Difluorophenethyl)piperidin-4-yl]-6-bromoindoline (1.8 g) wastreated as in Examples 136, 142, 145 and 147 to give the hydrochloride(0.12 g) of the title compound as a pale green powder (yield: 6.6%).

m.p. (hydrochloride): 241-243° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.85-2.05(4H, m), 2.89 (2H, t, J=8 Hz),3.03-3.18 (4H, m),3.21-3.43(4H, m), 3.49(2H, s), 3.64-3.77(3H, m), 6.52-6.59 (2H, m),6.98-7.10 (4H, m), 7.29-7.35 (1H, m), 7.59 (1H, br-s).

FAB-Mass: 400(MH+).

Fxample 226: Synthesis of1-{1-[3-(4-fluorophenyl)-propyl]piperdin-4-yl}-6-acetamidomethylindoline

1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and3-(4-fluorophenyl) propyl bromide (24 0 mg) were treated as in Example 2to give the title compound (220 mg) as pale yellow prisms (yield: 58%).

m.p.: 128-130° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.73-1.99(6H, m), 2.00(3H, s), 2.02-2.20(2H, m), 2.39-2.67(4H,m), 2.92(2H, t, J=8 Hz), 3.02-3.20(2H, m) 3.34-3.44(1H, m), 3.41(2H, t,J=8 Hz), 4.32(2H, d, J=6 Hz), 5.71 (1H, br-s), 6.33 (1H, s) 6.45 (1H, d,J=8 Hz), 6.94-7.00 (3H, m), 7.12-7.16(2H, m)

FAB-Mass: 410(MH+).

Example 227: Synthesis of1-{1-[4-4-fluorophenyl)butyl]-piperdin-4-yl}-6-acetamidomethylindoline

1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and4-(4-fluorophenyl)butyl bromide (250 mg) were treated as in Example 2 togive the title compound (280 mg) as white needles (yield: 70%).

m.p.: 119-121° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.50-1.68(4H, m), 1.70-1.84(4H, m) 1.99-2.12(2H, m), 2.00(3H, s),2.34-2.45(2H, m), 2.57-2.64(2H, m), 2.91(2H, t, J=8 Hz), 3.00-3.10(2H,m), 3.32-3.44(1H, m), 3.40(2H, t, J=8 Hz), 4.32(2H, d, J=6 Hz), 5.70(1H,br-s), 6.31(1H, s), 6.59(1H, d, J=8 Hz), 6.93-7.00(3H, m), 7.10-7.14(2H,m).

FAB-Mass: 424(MH+).

Example 228: Synthesis of1-[1-(4-methoxyphenethyl)-piperdin-4-yl]-6-methoxyindoline

1-(Piperidin-4-yl)-6-methoxyindoline (320 mg) and 4-methoxyphenethylbromide (360 mg) were treated as in Example 2 to give the oxalate (220mg) of the title compound as a white powder (yield: 34%).

m.p. (oxalate): 165-167° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.74-1.88(4H, m), 2.79(2H, t, J=8 Hz), 2.84-2.90(4H, m),3.03-3.12(2H, m), 3.30(2H, t, J=8 Hz), 3.47-3.69(3H, m), 3.67 (3H, s)3.71 (3H, s), 6.07-6.15 (2H, m), 6.84-6.93 (3H, m) 7.16-7.21(2H, m).

FAB-Mass: 367(MH+).

Example 229: Synthesis of1-[1-(4-methoxyphenethyl)-piperdin-4-yl]-6-fluoroindoline

1-(Piperidin-4-yl)-6-fluoroindoline (250 mg) and 4-methoxyphenethylbromide (290 mg) were treated as in Example 2 to give the hydrochloride(120 mg) of the title compound as a white powder (yield: 27%).

m.p. (hydrochloride): 212-214° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-1.92 (4H, m), 2.83 (2H, t, J=8 Hz), 2.90-2.97 (2H, m),3.00-3.10(2H, m), 3.17-3.26(2H, m), 3.38(2H, t, J=8 Hz), 3.60-3.73(3H,m), 3.72(3H, s), 6.24-6.29(1H, m), 6.36-6.40(1H, m), 6.87-6.97(3H, m),7.17-7.21(2H, m).

FAB-Mass: 355(MH+).

Example 230: Synthesis of1-[1-(4-sulfamoylphenethyl)-piperdin-4-yl]-6-methoxyindoline

1-(Piperidin-4-yl)-6-methoxyindoline (350 mg) and 4-sulfamoylphenethylbromide (340 mg) were treated as in Example 2 to give the title compound(70 mg) as a brown powder (yield: 13%).

m.p.: 179-182° C.

¹H-NMR (400 MHz, CDCL₃):

δ(ppm) 1.71-1.90(4H, m), 2.11-2.29(2H, m), 2.61-2.70 (2H, m),2.82-2.98(4H, m), 3.10-3.21(2H, m), 3.31-3.41(3H, m), 3.78(3H, s),4.98(2H, br-s), 6.00(1H, s), 6.12(1H, d, J=8 Hz), 6.94(1H, d, J=8 Hz),7.35(1H, d, J=8 Hz), 7.85(1H, d, J=8 Hz).

FAB-Mass: 416(MH+).

Example 231: Synthesis of1-[1-(4-fluorophenoxypropyl)-piperdin-4-yl]-6-bromoindoline

1-(Piperidin-4-yl)-6-bromoindoline (1.6 g) and 4-fluorophenoxypropylbromide (1.6 g) were treated as in Example 2 to give the title compound(2.2 g) as a white powder (yield: 90%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.51-1.85(2H, m), 1.87-1.89(2H, m), 1.92-2.19(4H, m),2.52-2.62(2H, m), 2.90(2H, t, J=8 Hz), 3.03-3.14(2H, m), 3.28-3.33(1H,m), 3.42(2H, t, J=8 Hz), 3.97(2H, t, J=6 Hz), 6.45(1H, s), 6.68(1H, d,J=8 Hz), 6.80-6.89(3H, m), 6.92-7.00(2H, m).Example 232: Synthesis of1-[1-(4-fluorophenoxypropyl)-piperdin-4-yl]-6-acetamidomethylindoline

1-[1-(4-Fluorophenoxypropyl)piperidin-4-yl]-6-bromoindoline (1.2 g) wastreated as in Examples 130, 131 and 133 to give the oxalate (46 mg) ofthe title compound as a brown hygroscopic amorphous solid (yield: 3.2%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.77-1.93(4H, m), 2.03-2.13(2H, m), 2.08(3H, s), 2.84(2H, t, J=8Hz), 2.85-2.99(2H, m),3.04-3.12(2H, m), 3.31(2H, t, J=8 Hz),3.44-3.53(2H, m), 3.60-3.69(1H, m), 4.03(2H, t, J=6 Hz), 4.13(2H, d, J=6Hz), 6.39(1H, s), 6.45(1H, d, J=8 Hz), 6.93-6.98(3H, m), 7.11-7.16(2H,m), 8.21(1H, t, J=6 Hz).

FAB-Mass: 426(MH+).

Example 233: Synthesis of1-{1-[2-(6-benzothiazolyl)ethyl]-piperdin-4-yl}-6-methoxyindoline

6-(2-Bromoethyl)benzothiazole (0.108 g) and1-(piperidin-4-yl)-6-methoxyindoline (0.105 g) were treated as inExample 2 to give the title compound (0.145 g) as a yellow oil (yield:81.9%).

Next, oxalic acid (37 mg) was added thereto to give a salt followed byrecrystallization from ethanol. Thus the oxalate (0.097 g) of the titlecompound was obtained.

m.p.: 188° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.87(4H, m), 2.82(2H, t, J=7.6 Hz), 3.21(2H, br-t), 3.18(2H, m),3.28(2H, m), 3.34(2H, t, J=7.6 Hz), 3.58(2H, m), 3.70(3H, s), 3.72(1H,m), 6.12(1H, d, J=7.6 Hz), 6.15(1H, s) 6.91(1H, d, J=7.6 Hz), 7.50(1H,d, J=8.4 Hz), 8.08(1H, d, J=8.4 Hz), 8.10(1H, s), 9.39(1H, s).

ESI-Mass: 394.2(MH+).

Example 234: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]thiazolo[5,4-f]indoline

Thiazolo[5,4-f]indoline (0.2 g), 1-(4-fluorophenethyl)-4-piperidone (0.6g), acetic acid (0.66 g) and triacetoxylated sodium borohydride (0.79 g)were treated as in Example 101 to give the hydrochloride (0.34 g) of thetitle compound as a yellow powder (yield: 71%).

m.p. (hydrochloride): 165° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.93-2.06 (4H, m), 2.98-3.06 (4H, m), 3.08-3.19 (2H, m),3.24-3.32 (2H, m), 3.43 (2H, t, J=8 Hz), 3.60-3.70 (2H, m), 3.81-3.90(1H, m), 7.16-7.20 (3H, m), 7.31-7.36 (2H, m), 7.70 (1H, S), 9.14 (1H,s).

FAB-Mass: 382(MH+)

Example 235: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-aminothiazolo[5,4]indoline

Bromine (0.22 ml) was added dropwise into a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminoindoline (1.2 g) andpotassium thiocyanate (1.0 g) in acetic acid (12 ml) and the resultantmixture was heated at 100° C. for 1 hr. Under ice cooling, a 5 N aqueoussolution of sodium hydroxide and chloroform were added to the reactionsolution and the layers were separated. The organic layer was washedwith brine and dried over anhydrous magnesium sulfate. Then the residuewas purified by silica gel column chromatography (methylenechloride/ethanol system) to give the title compound (0.20 g) as a brownpowder (yield: 14%).

m.p.: 173° C. (decomp.).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.68-1.90(2H, m), 2.07-2.16(2H, m), 2.55-2.61(2H, m),2.75-2.82(2H, m), 2.97(2H, t, J=8 Hz), 3.07-3.14(2H, m), 3.36-3.45(1H,m), 3.41(2H, t, J=8 Hz), 5.25(2H, br-s), 6.62(1H, s), 6.94-6.99(2H, m),7.14-7.19(3H, m).

FAB-Mass: 397(MH+).

Example 236: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-7-hydroxy-(4a,7a)-cyclohexanoindolineand1-[1-(4-fluorophenethyl)piperdin-4-yl]-4-hydroxy-(3b,6a)-cyclohexanoindolineand oxalates thereof

Under ice cooling, triethyl phosphonoacetate (2.24 g) was added dropwiseinto a suspension of 60% sodium hydride (0.4 g) in THF (30 ml). Afterthe completion of the evolution of hydrogen, a solution of1-(l-acetylpiperidin-4-yl)-indoline-7-carboxaldehyde (2.4 g) in THF (20ml) was added dropwise into the reaction solution and the resultantmixture was reacted at room temperature for 3 hr. Then the reactionsolution was partitioned between ethyl acetate and water followed bywashing with water, drying and concentration under reduced pressure.

The resulting residue was dissolved in ethanol (50 ml). After adding 10%palladium carbon (0.3 g) thereto, hydrogenation was carried out underatmospheric pressure. After the completion of the reaction, the reactionsolution was filtered through celite and washed with ethanol. A 5 Naqueous solution (5 ml) of sodium hydroxide was added to the filtrateand the resultant mixture was reacted at 50° C. for 1 hr. After coolingthe reaction solution, a 5 N aqueous solution (5 ml) of hydrochloricacid was added thereto followed by concentration under reduced pressure.Then methylene chloride (100 ml) was added to the residue and theresultant mixture was filtered through celite. The filtrate wasconcentrated.

To the resulting crude carboxylic acid (1.8 g) thus obtained was addedpolyphosphoric acid (30 g) and the resultant mixture was reacted at 120°C. for 2 hr. Next, the reaction solution was cooled to 50° C. and water(200 ml) was added thereto followed by extraction with ethyl acetate.The ethyl acetate layer was washed successively with water, a 10%aqueous solution of potassium carbonate, water and brine, dried andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/n-hexane system) to give amixture (0.31 g) of cyclopentanone derivatives as a colorless oil.

This mixture was dissolved in ethanol (15 ml). After adding an 8 Naqueous solution (5 ml) of sodium hydroxide thereto, the resultantmixture was heated under reflux for 6 hr. Then the reaction solution wasconcentrated under reduced pressure and the residue was partitionedbetween ethyl acetate and an aqueous solution of ammonium chloride. Theethyl acetate layer was washed with water, dried and concentrated underreduced pressure. The resulting residue was purified by silica gel shortcolumn chromatography (methylene chloride/methanol system) to give apale brown oil (0.21 g).

This oily mixture (0.20 g), 4-fluorophenethyl bromide (0.18 g) andpotassium carbonate (0.43 g) were suspended in DMF (15 ml) and thenreacted at 60° C. for 12 hr. The reaction solution was partitionedbetween ethyl acetate and water. The ethyl acetate layer was washed withwater and brine, dried and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(methylene chloride/methanol system) to give a mixture (0.12 g) ofketone derivatives as a colorless oil.

This mixture was dissolved in methanol and sodium borohydride was addedthereto at room temperature. After reacting for 30 min, the solvent wasevaporated under reduced pressure. Then the residue was partitionedbetween ethyl acetate and water. The ethyl acetate layer was washed withwater, dried and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (methylenechloride/methanol system) to give1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-hydroxy-(4a,7a)-cyclohexanoindoline(0.04 g) and1-[1-(4-fluorophenethyl)-piperidin-4-yl]-4-hydroxy-(3b,6a)-cyclohexanoindoline(0.03 g) each as a colorless oil. These compounds were each dissolved inmethanol and reacted with oxalic acid. After removing the solvent, etherwas added to the residue. The resulting precipitate was collected byfiltration and dried. Thus the oxalates of the title compounds wereobtained each as an amorphous solid.

(1)1-[1-(4-Fluorophenethyl)piperidin-4-yl]-7-hydroxy-(4a,7a)-cyclohexanoindoline

Oxalate

¹H-NMR (400 MHz, CD₃OD):

δ(ppm) 1.87(1H, m), 2.04(4H, m), 2.39(1H, m), 2.63(1H, m), 2.86(3H, m),3.02-3.25(4H, m), 3.30-3.40(4H, m), 3.70-3.85(3H, m), 5.06(1H, br-t),6.56(1H, s), 6.92(1H, s), 7.05(2H, t, J=8.0 Hz), 7.31(2H, br).

FAB-Mass: 381(MH+).

(2)1-[1-(4-Fluorophenethyl)piperidin-4-yl]-4-hydroxy-(3b,6a)-cyclohexanoindoline

Oxalate

¹H-NMR (400 MHz, CD₃OD):

δ(ppm) 1.87-2.06 (5H, m), 2.37 (1H, m), 2.65 (1H, m),2.93 (2H, m),3.02-3.23(5H, m), 3.30-3.40(4H, m), 3.70-3.84(3H, m), 5.15(1H, br-t),6.48(1H, d, J=8.0 Hz), 6.92(1H, d, J=8.0 Hz), 7.05(2H, t, J=8.0 Hz),7.32(2H, br-t).

FAB-Mass: 381(MH+).

Example 237: Synthesis of1-(1-methylpiperdin-4-yl)-6-(4-fluorobenzenesulfonylamino)indoline

6-(4-Fluorobenzenesulfonylamino) indoline (0.3 g), 1-methyl-4-piperidone(0.17 g), acetic acid (0.36 g) and triacetoxylated sodium borohydride(0.41 g) were treated as in Example 101 to give the hydrochloride (0.08g) of the title compound as a pale yellow powder (yield: 19%).

m.p. (hydrochloride): 170-172° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.63-1.71(2H, m), 1.80-1.94(2H, m), 2.71(3H, s), 2.76(2H, t, J=8Hz), 3.03-3.14(2H, m), 3.24(2H, t, J=8 Hz) 3.40-3.56 (3H, m) 6.18 (1H,d, J=8 Hz), 6.22 (1H, s), 6.81 (1H, d, J=8 Hz), 7.35-7.39(2H, m),7.69-7.78(2H, m).

FAB-Mass: 390(MH+).

Example 238: Synthesis of1-(1-ethylpiperdin-4-yl)6-(4-fluorobenzenesulfonylamino)indoline

6-(4-Fluorobenzenesulfonylamino)indoline (0.3 g), 1-ethyl-4-piperidone(0.19 g), acetic acid (0.36 g) and triacetoxylated sodium borohydride(0.41 g) were treated as in Example 101 to give the hydrochloride (0.34g) of the title compound as a pale yellow hygroscopic amorphous solid(yield: 77%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.22(3H, t, J=7 Hz),1.62-1.71(2H, m),1.80-1.99(2H, m), 2.76(2H,t, J=8 Hz), 2.95-3.19(4H, m), 3.22(2H, t, J=8 Hz), 3.48-3.80(3H, m),6.16(1H, d, J=8 Hz), 6.23(1H, s), 6.81(1H, d, J=8 Hz), 7.31-7.40(2H, m),7.70-7.80(2H, m).

FAB-Mass: 390(MH+).

Example 239: Synthesis of1-(1-ethylpiperdinyl)-4-(4-fluorophenyl)indoline

4-(4-Fluorophenyl)indoline (250 mg), 1-ethyl-4-piperidone (230 mg),acetic acid (430 mg) and triacetoxylated sodium borohydride (510 mg)were treated as in Example 1 to give the hydrochloride (200 mg) of thetitle compound as a white powder (yield: 46%).

m.p. (hydrochloride): 270° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.23 (3H, t, J=7 Hz), 1.83-2.04 (4H, m),2.91-3.12 (6H, m),3.24-3.34(2H, m), 3.50-3.57(2H, m), 3.70-3.80(1H, m), 6.54(1H, d, J=8Hz), 6.60(1H, d, J=8 Hz), 7.09(1H, t, J=8 Hz), 7.21-7.26(2H, m),7.45-7.48(2H, m), 9.89(1H, br-s).

FAB-Mass: 325(MH+).

Example 240: Synthesis of1-(1-ehtylpiperdin-4-yl)-3-(4-fluorophenyl)indoline

3-(4-Fluorophenyl)indoline (0.184 g) was treated as in Example 16 togive the title compound (0.102 g) as a yellow oil (yield: 38.0%).

Next, oxalic acid (14 mg) was added thereto to give a salt followed byrecrystallization from ethanol. Thus the oxalate (0.063 g) of the titlecompound was obtained.

m.p. (oxalate): 216° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.20(3H, t, J=6.8 Hz), 1.90(4H, m), 2.96(2H, m), 3.04(2H, m),3.23(1H, t, J=8.2 Hz), 3.48(2H, m), 3.75(2H, m), 4.42(1H, t, J=8.2 Hz),6.58(1H, t, J=7.6 Hz), 6.64(1H, d, J=7.6 Hz), 6.78(1H, d, J=7.6 Hz),7.06(1H, t, J=7.6 Hz), 7.14(2H, t, J=8.4 Hz), 7.28(1H, dd, J=5.6, 8.4Hz).

FAB-Mass: 325(MH+).

Example 241: Synthesis of1-(1-ethylpiperdin-4-yl)-3-(4-methoxyphenyl)indoline

Methoxymethyltriphenylphosphonium bromide (7.113 g) and 4-anisaldehyde(2.6 ml) were treated as in Production Example 41-1 to give a paleyellow, oil (2.235 g). Then this product was dissolved in isopropanol(25 ml) and 2 N hydrochloric acid (25 ml). After adding phenylhydrazine(1.0 ml), the resultant mixture was heated under reflux for 1 hr. Thenthe reaction solution was allowed to cool and concentrated under reducedpressure. Next, ethyl acetate was added thereto and the layers wereseparated. The organic layer was washed with saturated aqueous solutionof sodium bicarbonate and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/ethyl acetate system) togive a yellow oil (1.249 g) The resulting product was treated as inProduction Example 54 to give a yellow oil (0.534 g). Subsequently, thisproduct and 1-ethyl-4-piperidone were treated as in Example 16 to givethe title compound (0.307 g) as a yellow oil (yield: 4.4%).

Next, oxalic acid (41 mg) was added thereto to give a salt followed byrecrystallization from ethanol. Thus the oxalate (0.151 g) of the titlecompound was obtained as pale yellow crystals.

m.p. (oxalate): 143° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.20(3H, t, J=7.2 Hz), 1.89(4H, m), 2.95(2H, m), 3.04(2H, m),3.19(1H, t, J=8.4 Hz), 3.48(2H, m), 3.72(3H, s), 3.75(2H, m), 4.34(1H,t, J=8.4 Hz), 6.57(1H, t, J=7.6 Hz), 6.62(1H, d, J=7.6 Hz), 6.75(1H, d,J=7.6 Hz), 6.88(2H, d, J=8.8 Hz), 7.05(1H, t, J=7.6 Hz), 7 16(2H, t,J=8.8 Hz).

ESI-Mass: 337.1(MH+).

Example 242: Synthesis of1-(1-ethyl)piperdin-4-yl)-3-(4-methoxybenzyl)indoline

3-(4-Methoxybenzyl)indoline (0.332 g) and 1-ethyl-4-piperidone (0.28 ml)were treated as in Example 16 to give the title compound (0.380 g) as apale yellow oil (yield: 78.0%).

Next, oxalic acid (49 mg) was added thereto to give a salt followed byrecrystallization from acetone. Thus the oxalate (0.150 g) of the titlecompound was obtained.

m.p. (oxalate): 136° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.18(3H, t, J=7.6 Hz), 1.80(4H, m), 2.63(1H, dd, J=9.2, 13.6 Hz),2.89 (2H, m), 2.99 (4H, m), 3.23 (1H, t, J=8.6 Hz) 3.44(3H, m), 3.67(1H,m), 3.73(3H, s), 6.51(1H, d, J=7.6 Hz), 6.55(1H, t, J=7.6 Hz), 6.87(2H,d, J=8.4 Hz), 6.92(1H, d, J=7.6 Hz), 7.01(1H, t, J=7.6 Hz), 7.15(2H, d,J=8.4 Hz).

ESI-Mass: 351.3(MH+).

Example 243-1: Synthesis of1-(4-pyridylmethyl)-3-(4-methoxybenzyl)indoline

3-(4-Methoxybenzyl)indoline (2.0 g) and 4-pyridinecarboxyaldehyde (1.2ml) were treated as in Example 16 to give the title compound (1.474 g)as apaleyellowoil (yield: 53.44%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.27(1H, d, J=8.8, 14.0 Hz), 3.08(2H, m), 3.36(1H, t, J=8.8 Hz),3.55(1H, m), 3.79(3H, s), 4.20(2H, d, J=7.6 Hz), 7.00(1H, d, J=7.6 Hz),7.06(3H, m), 7.20(2H, m), 8.53(2H, dd, J=1.6, 4.8 Hz).Example 243-2: Synthesis of1-[(1-ethylpiperdin-3-en-4-yl)methyl]-3-(4-methoxybenzyl)indoline

1-(4-Pyridylmethyl)-3-(4-methoxybenzyl)indoline (0.7 g) was dissolved inacetonitrile (10 ml). After adding ethyl iodide (0.29 ml), the mixturewas heated in a sealed tube at 70 to 90° C. for 9 hr. After allowing tocool, the reaction solution was concentrated under reduced pressure.Then ethanol (20 ml) and sodium borohydride (0.40 g) were added to theresidue followed by stirring at room temperature for 1 hr. The reactionsolution was concentrated under reduced pressure, diluted with ethylacetate (200 ml), washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (0.115 g) as a pale yellow oil(yield: 15.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.12(3H, t, J=7.2 Hz), 2.14(2H, m), 2.48(2H, q, J=7.2 Hz), 2.56(2H, m), 2.73 (1H, dd, J=9.2, 14.4 Hz), 2.96 (2H, br-d), 3.01(2H, m),3.40(2H, t, J=9.2 Hz), 3.53(2H, br-s), 3.79 (3H, s),5.58 (1H, br-s),6.47 (1H, d, J=9.1 Hz), 6.61 (1H, d, J=9.1 Hz), 6.83 (2H, m), 6.83 (2H,m), 6.91 (1H, d, J=8.0 Hz), 6.47(1H, d, J=9.1 Hz), 7.07(3H, m).Example 243-1: Synthesis of1-[(1-ehtyl)piperdin-4-yl)methyl]-3-(4-methoxybenzyl)indoline

1-[(1-Ethylpiperidin-3-en-4-yl)methyl]-3-(4-methoxybenzyl)indoline(0.115 g) was dissolved in ethanol (3.2 ml). After adding a palladiumcarbon catalyst thereto, catalytic reduction was carried out underatmospheric pressure at room temperature for 54 hr. Then the catalystwas filtered off and the filtrate was concentrated under reducedpressure. The resulting residue was purified by NH-silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(0.053 g) as a pale yellow oil (yield: 45.8%).

Next, oxalic acid (6 mg) was added thereto to give a salt followed byrecrystallization from a solvent mixture of ethyl acetate with isopropylether. Thus the oxalate (0.313 g) of the title compound was obtained ascolorless crystals.

m.p. (oxalate): 78° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.17(3H, t, J=7.2 Hz), 1.38(2H, m), 1.82(2H, br-t), 2.64(1H, dd,J=8.6, 14.0 Hz), 2.75(2H, br-t), 2.83(1H, m), 2.97(4H, m), 3.29(1H, t,J=8.6 Hz), 3.34(2H, br-d), 3.45(1H, m), 3.73(3H, s), 6.48(1H, d, J=7.6Hz), 6.55(1H, t, J=7.6 Hz), 6.86(2H, d, J=8.4 Hz), 6.94(1H, d, J=7.6Hz), 6.99(1H, t, J=7.6 Hz), 7.14(2H, d, J=8.4 Hz).

FAB-Mass: 365(MH+).

Example 244: Synthesis of1-(1-wthylpiperdin-4-yl)-3-(4-fluorobenzyl)indoline

3-(4-Fluorobenzyl)indoline (1.163 g) and 1-ethyl-4-piperidone (1.0 ml)were treated as in Example 16 to give the title compound (1.614 g) as ayellow oil (yield: 93.7%).

Next, oxalic acid (21 mg) was added thereto to give a salt followed byrecrystallization from ethanol. Thus the oxalate of the title compoundwas obtained.

m.p. (oxalate): 203° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d6):

δ(ppm) 1.20(3H, t, J=7.2 Hz), 1.82(4H, m), 2.70(1H, dd, J=8.8, 13.2 Hz),2.90-3.07(6H, m), 3.26(1H, t, J=8.8 Hz), 3.41-3.50(3H, m), 3.68(1H, m),6.54(2H, m), 6.91(1H, d, J=7.6 Hz), 7.02(1H, t, J=7.6 Hz), 7.12(2H, t,J=8.8 Hz), 7.27(1H, dd, J=5.6, 8.8 Hz).

ESI-Mass: 339.2(MH+).

Example 245: Synthesis of1-(1-ethylpiperidin-4-yl)-3-(3-pyridylmethyl)indoline

3-(3-Pyridylmethyl)indoline (0.253 g) was treated as in Example 16 togive the title compound (0.233 g) as a yellow oil (yield: 71.0%).

Next, oxalic acid (65 mg) was added thereto to give a salt followed byrecrystallization from ethanol. Thus the oxalate (0.191 g) of the titlecompound was obtained (yield: 45.5%).

m.p. (oxalate): 149° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.20(3H, t, J=7.6 Hz), 1.83(4H, m), 2.76(1H, dd, J=8.8, 11.6 Hz),3.04(6H, m), 3.29(1H, t, J=8.8 Hz), 3.50(3H, m), 3.68(1H, m), 6.52(1H,d, J=7.6 Hz), 6.56(1H, t, J=7.6 Hz), 6.92(1H, d, J=7.6 Hz), 7.02(1H, t,J=7.6 Hz), 7.32(1H, dd, J=4.8, 8.0 Hz), 7.65(1H, dt, J=2.0, 8.0 Hz),8.43(2H, m).

ESI-Mass: 322.2(MH+).

Example 246: Synthesis of1-(1-ethylpiperidin-4-yl)-3-(3-methoxyphenethyl)indoline

3-(3-Methoxyphenethyl)indoline (0.133 g) was treated as in Example 16 togive the title compound (0.132 g) as a yellow oil (yield: 52.3%).

Next, hydrochloric acid was added thereto to give the hydrochloride ofthe title compound as a hygroscopic amorphous solid.

Hydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.26(3H, t, J=8.0 Hz), 1.74(1H, m), 1.86(2H, m), 2.07(3H, m),2.63(2H, t, J=8.0 Hz), 2.99-3.07(5H, m), 3.14(1H, m), 3.52(3H, t, J=8.0Hz), 3.72(1H, m), 3.74(3H, s), 6.59(2H, m), 7.02(1H, t, J=8.0 Hz),7.08(1H, d, J=8.0 Hz), 7.20(1H, d, J=8.0 Hz).

ESI-Mass: 365.2(MH+).

Example 247: Synthesis of1-(1-ethylpiperidin-4-yl)-3-(3-fluorophenethyl)indoline

3-(3-Fluorophenethyl)indoline (0.582 g) was treated as in Example 16 togive the title compound (0.641 g) as a yellow oil (yield: 66.2%).

Next, oxalic acid (68 mg) was added thereto to give a salt followed byrecrystallization from ethyl acetate. Thus the oxalate (0.313 g) of thetitle compound was obtained as colorless crystals.

m.p. (oxalate): 138° C.

Oxalate

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.22(3H, t, J=7.2 Hz), 1.72(1H, m), 1.89(4H, m), 2.07(1H, m),2.67(2H, t, J=8.4 Hz), 2.97(2H, br-t), 3.12(1H, m), 3.50(3H, t, J=8.4Hz), 3.70(1H, m), 6.53(1H, d, J=7.6 Hz), 6.58(1H, d, J=7.6 Hz), 7.00(2H,m), 7.06(1H, d, J=7.6 Hz), 7.09(2H, m), 7.32(1H, q, J=7.6 Hz).

ESI-Mass: 353.1(MH+).

Example 248: Synthesis of 1-[1-(4-fluorophenethyl)-piperidin-4-yl]indan

1-(Piperidin-4-yl)indan (300 mg) and 4-fluorophenethyl bromide (370 mg)were treated as in Example 2 to give the hydrochloride (250 mg) of thetitle compound as a white powder (yield: 46%).

m.p. (hydrochloride): 222-224° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.50-1.98(6H, m), 2.01-2.12(1H, m), 2.72-2.94(4H, m),2.98-3.04(2H, m), 3.08-3.22(3H, m), 3.46-3.57(2H, m), 7.11-7.22(6H, m),7.28-7.31(2H, m), 10.33(1H, br-s).

FAB-Mass: 324(MH+).

Example 249: Synthesis of 1-1-(4-methoxyphenethyl)-piperidin-4-yl]indan

1-(Piperidin-4-yl)indan (300 mg) and 4-methoxyphenethyl bromide (390 mg)were treated as in Example 2 to give the hydrochloride (260 mg) of thetitle compound as a white powder (yield: 47%).

m.p. (hydrochloride): 191° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.48-1.57(1H, m), 1.60-1.97(5H, m), 2.01-2.11(1H, m),2.71-3.00(6H, m), 3.08-3.18(3H, m), 3.45-3.56(2H, m), 3.70(3H, s),6.87(2H, d, J=8 Hz), 7.11-7.23(6H, m), 10.43(1H, br-s).

FAB-Mass: 336(MH+).

Example 250: Synthesis of1-{4-[2-(4-fluorophenyl)ethyl]-piperazin-1-yl}-6-methoxyindanhydrochloride

(250-1) 1-(Piperazin-1-yl)-6-mehoxyindan

1-(4-Acetylpiperazin-1-yl)-6-methoxyindan (2.20 g) obtained as anintermediate in the above Example and an 8 N aqueous solution (8.0 ml)of sodium hydroxide were heated under reflux in ethanol. Then thereaction mixture was concentrated under reduced pressure, extracted withmethylene chloride, dried and concentrated under reduced pressure again.The resulting residue was purified by silica gel column chromatography(methylene chloride/methanol system) to give the title compound (1.48 g)as a wax (yield: 73%).(250-2) 1-[4-(4-Fluorophenacyl)piperazin-1-yl]-6-methoxyindan

In the presence of a 5 N aqueous solution (2.0 ml) of sodium hydroxide,1-(piperazin-1-yl)-6-methoxyindan (0.41 g) and 4-fluorophenacyl chloride(0.46 g) were reacted in methylene chloride at 0° C. Then, the reactionmixture was extracted with methylene chloride. The methylene chloridelayer was washed with water, dried and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (toluene/acetone system) to give the title compound (0.60g).(250-3) 1-(4-[2-(4-Fluorophenyl)ethyllpiperazin-1-yl]-6-methoxyindanhydrochloride

Lithium aluminum hydride (0.13 g) was suspended in THF. Into theresultant suspension was added dropwise a solution of1-[4-(4-fluorophenacyl)piperazin-1-yl]-6-methoxyindan (0.60 g) in THFand the reaction mixture was heated under reflux while monitoring thereaction by TLC. Then the reaction solution was ice cooled and water(0.13 ml), a 5 N aqueous solution (0.13 ml) of sodium hydroxide andwater (0.39 ml) were successively added thereto followed by stirring atroom temperature for 1 hr. The resulting precipitate was filtered offand washed with THF. The filtrate was concentrated under reducedpressure and the resulting residue was purified by silica gel columnchromatography (methylene chloride/methanol system) to give an oil (0.48g) (yield: 83%).

This oily product was converted into a hydrochloride in a conventionalmanner to give the title compound as a white powder.

m.p.: 213° C. (decomp.).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.03-2.19(2H, m), 2.49-2.66(10H, m), 2.69-2.90(4H, m), 3.80(3H,s), 4.32(1H, t, J=7.2 Hz), 6.77(1H, dd, J=8.4, 2.8 Hz), 6.90(1H, d,J=2.8 Hz), 6.93-6.99(2H, m), 7.11(1H, d, J=8.4 Hz), 7.12-7.17(2H, m).

FAB-Mass: 355(MH+).

Example 251; Synthesis of 1-(4-ethylpiperazin-1-yl)-6-methoxyindanhydrochloride

(251-1) 1-Chloro-6-mehtoxyindan

6-Methoxyindan-1-one (5.0 g) was dissolved in methanol (50 ml). Next,sodium tetrahydroborate (1.41 g) was added thereto at 0° C., and theresultant mixture was reacted at room temperature for 5 hr. The reactionsolution was concentrated under reduced pressure and the residue waspartitioned between ethyl acetate and water. The ethyl acetate layer waswashed with water, dried and concentrated under reduced pressure to give6-methoxyindan-1-ol (5.1 g) as an oil. This alcohol was not purified butreacted as such with thionyl chloride (4.5 ml) in ether at roomtemperature for 6 hr. The reaction solution was poured into ice waterand extracted with ether. The ether layer was washed with water, driedand concentrated under reduced pressure to give the title compound (2.76g).(251-2) 1-(4-Acetylpiperazin-1-yl)-6-methoxyindan

1-Chloro-6-methoxyindan (2.76 g), 1-acetylpiperazine (2.30 g) andpotassium carbonate (2.90 g) were heated under reflux in acetoneovernight. Then the reaction solution was cooled, filtered and washedwith acetone. The filtrate was concentrated under reduced pressure andthe residue was partitioned between ethyl acetate and water. The ethylacetate layer was washed with water, dried and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (toluene/acetone system) to give the titlecompound (2.70 g) as an oil.(251-3) 1-(4-Ethylpiperazin-1-yl)-6-methoxyindan hydrochloride

Lithium aluminum hydride (0.14 g) was suspended in THF. Into theresultant suspension was added dropwise a solution of1-(4-acetylpiperazin-1-yl)-6-methoxyindan (0.50 g) in THF and thereaction mixture was heated under reflux while monitoring the reactionby TLC. Then the reaction solution was ice cooled and water (0.14 ml), a5 N aqueous solution (0.14 ml) of sodium hydroxide and further water(0.42 ml) were successively added thereto followed by stirring at roomtemperature for 1 hr. The resulting precipitate was filtered off andwashed with THF. The filtrate was concentrated under reduced pressureand the obtained residue was purified by silica gel columnchromatography (methylene chloride/methanol system) to give1-(4-ethylpiperazin-1-yl)-6-methoxyindan (0.30 g) as an oil (yield:63%).

This oily product was converted into a hydrochloride in a conventionalmanner to give the title compound as a white powder.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.08(3H, t, J=7.2 Hz), 2.02-2.19(2H, m), 2.41(2H, q, J=7.2 Hz),2.43-2.65(8H, m), 2.69-2.90(2H, m), 3.80(3H, s), 4.92(1H, t, J=7.2 Hz),6.77(1H, dd, J=8.4, 2.8 Hz), 6.90(1H, d, J=2.8 Hz), 7.09(1H, d, J=8.4Hz).

FAB-Mass: 261(MH+).

Example 252: Synthesis oftrans-1-(4-ethylpiperazin-1-yl)-2-ethoxycarboxyaminoindan

A mixture of (±)-(Z)-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (1.4g) synthesized in accordance with the method described in WO95/04028,ethylpiperazine (1.3 ml), scandium trifluoromethanesulfonate (50 mg) andtoluene (40 ml) was stirred under nitrogen atmosphere at 70° C. for 17hr as in Example 13 of WO95/04028 and Tetrahedron Lett., 1627-1628,35(1994). After allowing to cool to room temperature again, ethylacetate and water were added to the reaction solution and the layerswere separated. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresulting residue was purified by Chromatorex NH-silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(675 mg) (yield: 31%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.07(3H, t, J=7.2 Hz), 1.23(3H, m), 2.40(2H, q, J=7.2 Hz),2.45(4H, br-s), 2.68(6H, m), 3.37(1H, dd, J=16.2, 7.4 Hz), 4.02(1H, d,J=4.8 Hz), 4.12(2H, m), 7.16-7.23(3H, m), 7.33(1H, m).Example 253: Synthesis oftrans-1-(4-ethylpiperazin-1-yl)-2-methylaminoindan

trans-1-(4-Ethylpiperazin-1-yl)-2-ethoxycarboxyaminoindan (670 mg) wasdissolved in dry ether (20 ml) and lithium aluminum hydride (401 mg) wasadded thereto at room temperature. Under nitrogen atmosphere, themixture was stirred for 21 hr. Then water (0.4 ml), a 5 N aqueoussolution (0.4 ml) of sodium hydroxide and further water (1.2 ml) weresuccessively added thereto followed by stirring. Thereaction solutionwas filtered through celite and the filtrate was concentrated underreduced pressure to give the title compound (503 mg).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.08(3H, t, J=7.2 Hz), 2.42(2H, q, J=7.2 Hz), 2.47(4H, m),2.69(5H, m), 3.18(1H, dd, J=16.2, 7.4 Hz), 3.48(1H, dt, J=7.4, 4.8 Hz),4.03(1H, d, J=4.8 Hz), 7.14-7.21(3H, m), 7.36(1H, m).Example 254: Synthesis oftrans-1-(4-ethylpiperazin-1-yl)-2-[methyl-(4-trifluorobenzyl)amino]indan

N-Methylamine (500 mg), 4-fluorobenzaldehyde (0.52 ml), acetic acid (0.6ml) and methylene chloride (20 ml) were treated as in Example 101 togive the title compound (670 mg) (yield: 95%).

Next, this product was dissolved in ethyl acetate (10 ml) anda solution(2 ml) of 4 NHCl in ethyl acetate was added thereto. After concentratingthe solvent under reduced pressure, ether was added to the residuefollowed by concentration. Then, it was dried in vacuo to give thehydrochloride (821 mg) of the title compound as white crystals.

Free

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.08(3H, t, J=7.2 Hz), 2.10(3H, s), 2.41(2H, q, J=7.2 Hz),2.45(4H, br-s), 2.64(4H, br-s), 2.95(2H, m), 3.48(3H, s), 3.73(1H, ddd,J=7.4, 7.2, 4.4 Hz), 4.33(1H, d, J=4.4 Hz), 6.98(2H, m), 7.19(3H, m),7.29(3H, m), 7.36(1H, m).

HCl salt

m.p.: 196-198° C.

FAB-Mass: 368 (MH+).

Example 255; Synthesis of 7-[4-hydroxy-1-(4-fluorophenethylpiperidin-4-yl]-5.6-dihydro-7H-pyrindine

6,7-Dihydro-5H-cyclopenta[B]pyridine (1.00 g, CAS Registry No. 533-37-9)was dissolved in tetrahydrofuran (15 ml). Under a stream of nitrogen, a1.6 M solution (5.8 ml) of n-butyllithium in hexane was added dropwiseinto the resultant solution while cooling to −55° C. or below. Afterstirring for 5 min, a solution of 1-(4-fluorophenethyl)-4-piperidone(2.04 g) in tetrahydrofuran (10 ml) was added dropwise thereinto at thesame temperature over 20 min. After stirring for 30 min, the reactionsolution was allowed to warm to room temperature again and water wasadded thereto. Then it was extracted with ethyl acetate and the organiclayer was washed with brine and dried over magnesium sulfate. Afterevaporating the solvent, the resulting residue (3.17 g) was purified bysilica gel column chromatography (methanol/methylene chloride system) togive the title compound (600 mg) as a slight brown oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.72-2.08(4H, m), 2.22-3.10(12H, m), 3.37(1H, d, J=9.5 Hz),5.81(1H, br-s), 6.93-7.01(2H,m), 7.08(1H, dd, J=8.0, 5.5 Hz),7.12-7.20(2H, m), 7.33(1H, d, J=8.0 Hz), 8.28(1H, d, J=5.5 Hz).

FAB-Mass: 341(MH+).

Example 256: Synthesis of7-[1-(4-fluorophenethyl)piperidin-4-ylidene]-5,6-dihydropyrindine

7-[4-Hydroxy-1-(4-fluorophenethyl)piperidin-4-yl]-5,6-dihydro-7H-pyrindine(350 mg) was dissolved in tetrahydrofuran (3 ml). Under ice cooling,thionyl chloride (0.11 ml) and triethylamine (0.50 ml) were addeddropwise thereinto. Then the resultant mixture was stirred at roomtemperature for 15 minutes f ollowed by addition of water. Next, themixture was extracted with ethyl acetate and the organic la yer waswashed with brine and dried over magnesium sulfate. After removing thesolvent, the resulting residue (250 mg) was purified by silica gelcolumn chromatography (hexane/ethyl acetate system) to give the titlecompound (45 mg) as an oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.45-2.50(2H, m), 2.58-2.68(6H, m), 2.75-2.95(6H, m), 3.48(2H,br-s), 6.93-7.00(3H, m), 7.14-7.20(2H, m), 7.48(1H, d, J=7.6 Hz),8.40(1H, d, J=4.4 Hz).

FAB-Mass: 323(MH+).

Example 257: Synthesis of7-[1-(4-fluorophenethyl)piperidin-4-yl]-5,6-dihydro-7H-pyrindine

7-[1-(4-Fluorophenethyl)piperidin-4-ylidene]-5,6-dihydropyrindine (100mg) was dissolved in methanol (5 ml). After adding two drops of aceticacid thereinto, the resultant mixture was vigorously shaken in thepresence of a palladium catalyst under a hydrogen gas pressure of 3kg/cm² for 12 hr. After filtering off the catalyst, water was added tothe reaction mixture followed by extraction with ethyl acetate. Theorganic layer was washed with brine a and dried over magnesium sulfate.Then the solvent was distilled away to give the title compound (45 mg)as an oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.22-1.52(2H, m), 1.94-2.40(4H, m), 2.55-2.96(4H, m),3.00-3.30(6H, m), 3.45-3.70(2H, m), 6.97-7.02(2H, m), 7.07(1H, dd,J=5.2, 7.6 Hz), 7.19-7.25(2H, m), 7.52(1H, d, J=7.6 Hz), 8.34(1H, d,J=5.2 Hz).

FAB-Mass: 325(MH+).

Example 258: Synthesis of7-[4-(4-fluorophenethyl)piperazin-1-yl]-5,6-dihydro-7H-pyrindine

7-Hydroxy-6,7-dihydro-5H-cyclopenta[B]pyridine (247 mg) synthesized inaccordance with the method described in JP-A 1-211581 was dissolved inmethylene chloride (5 ml). Under ice cooling, thionyl chloride (0.147ml) was added to the resultant solution and the resultant mixture wasstirred for 25 min. Then the reaction solution was evaporated to drynessunder reduced pressure. To the residue were added a solution of1-(4-fluorophenethyl)piperazine (570 mg) synthesized in accordance withthe method described in JP-A 54-92979 in dimethylformamide (5 ml) andtriethylamine (0.38 ml) followed by heating at 60° C. for 5 hr. Afteradding water, the reaction solution was extracted with ethylacetate. Theorganic layer was washed with brine and dried over magnesium sulfate.After evaporating the solvent, the resulting residue was purified byNH-silica gel column chromatography (hexane/methylene chloride system)to give the title compound (200 mg) as an oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.15-2.25(2H, m), 2.50-3.00(14H, m), 4.28(1H, t, J=7.0 Hz),6.92-7.00(2H, m), 7.08(1H, dd, J=5.0, 7.4 Hz), 7.12-7.18(2H, m),7.50(1H, d, J=7.4 Hz), 8.46(1H, d, J=5.0 Hz)

FAB-Mass: 326(MH+).

Example 259-1: Synthesis of cis- andtrans-2,6-dichloro-3-methoxyethylenylpyridines

Potassium t-butoxide (22.2 g) was added to a solution ofmethoxymethyltriphenylphosphonium chloride (62.5 g) in tetrahydrofuran(250 ml) and the resultant mixture was stirred at 0° C. for 20 min. Intothe resultant solution was added dropwise a solution of2,6-dichloro-3-formylpyridine (24.7 g) synthesized in accordance withthe method described in J. CHEM. SOC. PERKIN TRANS. 1 (1990, No. 9, p.2409.) in tetrahydrofuran (100 ml) followed by stirring for 2 hr. Thenwater and ethyl acetate were added to the reaction solution and thelayers were separated. The organic layer was washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. The resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give a mixture (21.5 g)of the geometrical isomers of the title compound as a pale yellow oil(yield: 75%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.71(3H, s), 3.82(3H, s), 5.53(1H, d, J=7 Hz), 5.93(1H, d, J=12Hz), 6.38(1H, d, J=7 Hz), 7.03(1H, d, J=12 Hz), 7.17(1H, d, J=8 Hz),7.19(1H, d, J=8 Hz), 7.60(1H, d, J=8 Hz), 8.36(1H, d, J=8 Hz).Example 259-2: Synthesis of 2.6-dichloro-3-formylmethylpyridine

A solution of cis- and trans-2,6-dichloro-3-methoxyethylenylpyridines(21.5 g) and 35% perchloric acid (100 ml) in ether (200 ml) was stirredat room temperature for a day. Then the reaction solution was basifiedby adding a conc. aqueous solution of sodium hydroxide and ethyl acetatewas added thereto and the layers were separated. The organic layer waswashed with brine and dried over magnesium sulfate. After evaporatingthe solvent, the resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(15 g) as a pale yellow oil (yield: 56%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.90(2H, s), 7.31(1H, d, J=8 Hz), 7.55(1H, d, J=8 Hz), 9.81(1H,s).Example 259-3: Synthesis of 2,6-dichloro-3-hydroxyethylpyridine

A solution of cis- and trans-2,6-dichloro-3-methoxyethylenylpyridines(2.0 g) and 35% perchloric acid (10 ml) in ether (30 ml) was stirred atroom temperature for a day. Then the reaction solution was basified byadding a conc. aqueous solution of sodium hydroxide and ethyl acetatewas added thereto and the layers were separated. The organic layer waswashed with brine and dried over magnesium sulfate. After evaporatingthe solvent, ethanol (20 ml) and sodium borohydride (0.076 g) were addedto the residue and the resultant mixture was stirred at room temperaturefor 1 hr. Then the reaction solution was concentrated under reducedpressure, diluted with a saturated aqueous solution of sodiumhydrogencarbonate and ethyl acetate and the layers were separated. Theorganic layer was washed with brine and dried over magnesium sulfate.After evaporating the solvent, the obtained residue was purified bysilica gel column chromatography (hexane/ethyl acetate system) to givethe title compound (1.3 g) as a pale yellow oil (yield: 69%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.50(1H, t, J=6 Hz), 2.99(2H, t, J=6 Hz), 3.95(1H, q, J=6 Hz),7.23(1H, d, J=8 Hz), 7.62(1H, d, J=8 Hz).Example 259-4: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloro-7-azaindoline

Under ice cooling, methanesulfonyl chloride (0.45 g) was added dropwiseinto a solution of 2,6-dichloro-3-hydroxyethylpyridine (0.65 g) inpyridine (10 ml) and the resultant mixture was stirred for 3 hr. Thenthe reaction solution was concentrated under reduced pressure, dilutedwith a saturated aqueous solution of sodium bicarbonate and ethylacetate and the layers were separated. The organic layer was washed withbrine and dried over magnesium sulfate. After evaporating the solvent,1-(4-fluorophenethyl)-4-aminopiperidine (0.75 g) and dichlorobenzene (20ml) were added to the residue and the resultant mixture was heated at180° C. for 2 hr. The reaction solution was concentrated under reducedpressure, diluted with a saturated aqueous solution of sodiumbicarbonate and ethyl acetate and the layers were separated. The organiclayer was washed with brine and dried over magnesium sulfate. Afterevaporating the solvent, the resulting residue was purified by NH-silicagel column chromatography (hexane/ethyl acetate system) to give thetitle compound (0.43 g) as a colorless oil (yield: 35%).

A portion of this product was converted into a hydrochloride in aconventional manner to give the title compound as a white powder.

m.p. (hydrochloride): 225° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90(2H, m), 1.99-2.10(2H, m), 2.93(2H, t, J=8 Hz),3.00-3.08(2H, m), 3.10-3.27(4H, m), 3.52(2H, t, J=8 Hz), 3.55-3.64(2H,m), 4.00-4.12(1H, m), 6.44(1H, d, J=8 Hz), 7.12-7.20(2H, m), 7.23(1H, d,J=8 Hz), 7.29-7.34(2H, m).

FAB-Mass: 360(MH+).

Example 260: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-azaindoline

2-Chloro-3-formylpyridine (1.5 g) synthesized in accordance with themethod described in J. CHEM. SOC. PERKIN TRANS. 1 (1990, No. 9, P.2409.) was treated as in Examples 259-1, 259-3 and 259-4 to give thehydrochloride (0.21 g) of the title compound as a white powder (yield:4.9%).

m.p. (hydrochloride): 223° C. (decomp.)

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.79-2.00(2H, m), 2.03-2.21(2H, m), 2.95-3.10(4H, m),3.22-3.36(4H, m), 3.60-3.69(4H, m), 4.15-4.24(1H, m), 6.51-6.60(1H, m),7.12-7.20(2H, m), 7.29-7.37(3H, m), 7.67-7.73(1H, m).

FAB-Mass: 326(MH+).

Example 261-1: Synthesis of 2,6-(difluoro-3-bromoethylpyridine

Under ice cooling, triphenylphosphine (3.1 g) and N-bromosuccinimide(1.9 g) were added to a solution of 2,6-difluoro-3-hydroxyethylpyridine(1.58 g) obtained as in Example 259-3 in methylene chloride (100 ml) andthe resultant mixture was stirred for 2 hr. After concentrating theresultant mixture under reduced pressure, the residue was purified bysilica gel column chromatography (hexane/ethyl acetate system) to givethe title compound (1.6 g) as a colorless oil (yield: 73%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 3.20(1H, t, J=6 Hz), 3.59(2H, t, J=6 Hz), 6.80-6.85(1H, m),7.75-7.83(1H, m).Example 261-2: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoro-7-azaindoline

A mixture of 2,6-difluoro-3-bromoethylpyridine (0.3 g),1-(4-fluorophenethyl)-4-aminopiperidine (0.3 g), triethylamine (0.27 g)ando-dichlorobenzene (20 ml) was heated at 180° C. for 2 hr. Then thereaction solution was concentrated under reduced pressure, diluted witha saturated aqueous solution of sodium hydrogencarbonate and ethylacetate and the layers were separated. The organic layer was washed withbrine and dried over magnesium sulfate. After evaporating the solvent,the resulting residue was purified by silica gel column chromatography(hexane/ethyl acetate system) followed by conversion into ahydrochloride in a conventional manner to give the hydrochloride (0.14g) of the title compound as a white powder (yield: 30%).

m.p. (hydrochloride): 202-204° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.90(2H, m), 1.99-2.11(2H, m), 2.91(2H, t, J=8 Hz),3.00-3.19(4H, m), 3.20-3.30(2H, m), 3.51(2H, t, J=8 Hz), 3.58-3.65(2H,m), 3.93-4.03(1H, m), 6.03(1H, d, J=8 Hz), 7.14-7.21(2H, m),7.29-7.35(3H, m).

FAB-Mass: 344(MH+).

Example 262: Synthesis of1-[1-(2,4-difluorophenethyl)-piperidin-4-yl]-6-chloro-7-azaindoline

1-(Piperidin-4-yl)-6-chloro-7-azaindoline (0.5 g) and2,4-difluorophenethyl bromide (0.43 g) were treated as in Example 2 togive the hydrochloride (74 mg) of the title compound as a brown powder(yield: 7.8%).

m.p. (hydrochloride): 221° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.81-1.91(2H, m), 2.00-2.15(2H, m), 2.91(2H, t, J=8Hz),3.03-3.39(6H, m),3.53(2H, t, J=8 Hz),3.60-3.68(2H, m), 4.01-4.12(1H,m), 6.46(1H, d, J=8 Hz), 7.08-7.17(1H, m), 7.21-7.31(2H, m),7.40-7.48(1H, m).

FAB-Mass: 378(MH+).

Example 263: Synthesis of1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-chloro-7-azaindoline

1-(Piperidin-4-yl)-6-chloro-7-azaindoline (0.8 g) and 4-methoxyphenethylbromide (0.72 g) were treated as in Example 2 to give the hydrochloride(220 mg) of the title compound as a pale yellow powder (yield: 16%).

m.p. (hydrochloride): 199° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.82-1.91(2H, m), 1.97-2.09(2H, m), 2.89-2.98(4H, m),3.08-3.24(4H, m), 3.52(2H, t, J=8 Hz), 3.56-3.64(2H, m), 4.00-4.10(1H,m), 6.44(1H, d, J=7 Hz), 6.90(1H, d, J=9 Hz), 7.18(1H, d, J=9 Hz),7.22(1H, d, J=7 Hz).

FAB-Mass: 372(MH+).

Example 264: Synthesis of1-[1-(4-fluorophenethyl)-piperdin-4-yl]-6-azaindoline

Under a stream of hydrogen, a mixture of 6-azaindoline (180 mg)synthesized in accordance with the method described in Tetrahedron,(1988, vol. 44, No. 10, p. 2977.), 1-(4-fluorophenethyl)-4-piperidone(530 mg), platinumoxide (20 mg), acetic acid (0.5 ml) and ethanol (10ml) was catalytically reduced at ordinary temperature under atmosphericpressure. After stirring the reaction mixture overnight, the catalystwas filtered off and the filtrate was concentrated under reducedpressure. The resulting residue was diluted with a saturated aqueoussolution of sodium hydrogencarbonate and ethyl acetate and the layerswere separated. The organic layer was washed with brine and dried overanhydrous magnesium sulfate and the resulting residue was purified byNH-silica gel column chromatography (hexane/ethyl acetate system)followed by conversion into an oxalate in a conventional manner to givethe oxalate (35 mg) of the title compound as a pale yellow powder(yield: 5.2%).

m.p. (oxalate): 196-198° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.83-1.91(4H, m), 2.90-3.05(6H, m), 3.18-3.27(2H, m), 3.38(2H, t,J=8 Hz), 3.51-3.60(2H, m), 3.69-3.79(1H, m), 7.10(1H, d, J=5 Hz),7.14-7.19(2H, m), 7.30-7.34(2H, m), 7.83(1H, d, J=5 Hz), 7.86(1H, s).

FAB-Mass: 326(MH+).

Example 265: Synthesis of5-[1-(4-fluorophenethyl)piperidin-4-ylidenel-7-methyl-5,6-dihydrocyclopentapyrazine

5-Methyl-6,7-dihydro-5(H)-cyclopenta[B]pyrazine (2.82 g, CAS RegistryNo. 23747-48-0) was dissolved in tetrahydrofuran (30 ml). Under a streamof nitrogen, a 1.6 M solution (13.4 ml) of n-butyllithium in hexane wasadded dropwise into the resultant solution while cooling to −55° C. orbelow. After stirring for 5 min, a solution of1-(4-fluorophenethyl)-4-piperidone (3.72 g) in tetrahydrofuran (10 ml)was added dropwise thereinto at the same temperature over 5 min. Afterstirring for 5 min, the reaction solution was allowed to warm to roomtemperature and water was added thereto. Then it was extracted withethyl acetate and the organic layer was washed with brine and dried overmagnesium sulfate. After evaporating the solvent, the resulting residue(6.5 g) was purified by NH-silica gel column chromatography(hexane/ethyl acetate system) to give an isomer A (1.48 g) and anotherisomer B (2.94 g) of5-[4-hydroxy-1-(4-fluorophenethyl)piperidin-4-yl]-7-methyl-5,6-dihdyro-5H-cyclopentapyrazineeach as an oil.

Isomer A:

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.40(3H, d, J=6.8 Hz), 1.48-1.85(5H, m), 2.47-2.65(5H, m),2.72-2.85(4H, m), 3.14-3.24(1H, m), 3.32-3.38(1H, m), 4.48(1H, s),6.93-7.00(2H, m), 7.12-7.19(2H, m), 8.24(1H, dd, J=1.2, 2.8 Hz),8.36(1H, dd, J=1.2, 2.8 Hz).

Isomer B:

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.33(3H, d, J=7.2 Hz), 1.65-1.97(5H, m), 2.27-2.86(9H, m),3.25-3.36(1H, m), 3.38-3.44(1H, m), 4.11(1H, s), 6.93-7.01(2H, m),7.12-7.20(2H, m), 8.27(1H, dd, J=0.8, 2.8 Hz), 8.36(1H, dd, J=0.8, 2.8Hz).

The above isomer A (1.48 g) was dissolved in acetic acid (10 ml). Thenconc. sulfuric acid (2.0 ml) was added thereto while cooling in a waterbath and the resultant mixture was stirred at room temperature for 2 hr.The reaction solution was basified with 10% potassium carbonate andextracted with ethyl acetate. The organic layer was washed with brineand dried over magnesium sulfate. After evaporating the solvent, theresulting residue was purified by NH-silica gel column chromatography(hexane/ethyl acetate system) to give the title compound (680 mg) as anoil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.38(3H, d, J=6.8 Hz), 2.12-2.40(1H, m), 2.45-2.50(2H, m),2.56-2.69(6H, m), 2.79-2.86(2H,m), 3.06-3.14(1H, m), 3.20-3.30(1H, m),3.33-3.39(1H, m), 6.94-7.00(2H, m), 7.15-7.19(2H, m), 8.18(1H, d, J=2.7Hz), 8.36(1H, dd, J=0.8, 2.7 Hz).

FAB-Mass: 338(MH+).

Example 266: Synthesis of5-[1-(4-fluorophenethyl)-piperidin-4-yl]-7-methyl-5,6-dihydro-5H-cyclopentapyrazine

5-[1-(4-Fluorophenethyl)piperidin-4-ylidene]-7-methyl-5,6-dihydrocyclopentapyrazine(300 mg) was dissolved in methanol (10 ml). After adding five drops ofacetic acid thereinto, the resultant mixture was vigorously shaken inthe presence of a palladium catalyst under a hydrogen gas pressure of4.2 kg/cm² for 13 hr. After filtering off the catalyst, water was addedto the reaction mixture followed by extraction with ethyl acetate. Theorganic layer was washed with brine and dried over magnesium sulfate.Then the solvent was evaporated to give the oily title compound (200 mg)as a mixture of stereoisomers (about 5:1).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.34(d, J=7.2 Hz) and 1.40(d, J=6.8 Hz)1:5 corresponding to 3H intotal, 1.44-1.56(3H, m), 1.62-1.90(2H, m), 2.00-2.20(3H, m),2.43-2.51(1H, m), 2.54-2.66(2H, m), 2.76-2.88(2H, m), 3.04-3.20(4H, m),6.93-7.00(2H, m), 7.13-7.19(2H, m), 8.30(s) and 8.31(s)5:1 correspondingto 2H in total.

FAB-Mass: 340(MH+).

Example 267: Synthesis of1-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinolinehydrochloride

A solution of 1-(4-piperidinyl)-7-methoxy-1,2,3,4-tetrahydroquinoline(250 mg), 2-(4-methoxyphenyl)ethyl bromide (260 mg) anddiisopropylethylamine (270 mg) in DMF (5 ml) was heated at 60° C. for 12hr under stirring. After the completion of the reaction, the reactionsolution was cooled to room temperature and water was added theretofollowed by extraction with ethyl acetate. The ethyl acetate layer waswashed with brine and dried over magnesium sulfate. After evaporatingthe solvent, the resulting obtained residue was purified by silica gelcolumn chromatography (toluene/acetone system) to give1-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinolineas an oil. This free compound was dissolved in ethyl acetate and 8.5%HCl/ethyl acetate was added thereto. The resulting hydrochloride wasrecrystallized from ethanol/ether to give the title compound (225 mg)(yield: 53%).

m.p.: 232-235° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.72-1.84(4H, m), 2.10-2.24(2H, m), 2.57(2H, t, J=6.0 Hz),2.96-3.03(2H, m), 3.09(2H, t, J=5.6 Hz), 3.11-3.21(4H, m), 3.58(2H,br-d), 3.66(3H, s), 3.71(3H, s), 3.90-4.00(1H, m), 6.11(1H, dd, J=8.4,2.4 Hz), 6.28(1H, d, J=2.4 Hz), 6.78(1H, d, J=8.4 Hz), 6.89(2H, d, J=8.4Hz), 7.18(2H, d, J=8.4 Hz), 10.68-10.81(1H, br-s).

MS: 381(M+H)+.

Next, the procedure of Example 267 was repeated to give the products ofExamples 268 to 274.Example 268:1-{1-[2-(4-Fluorophenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinolinehydrochloride

(Yield: 75%).m.p.: 258° C. (decomp.).¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.74-1.84(4H, m), 2.23(2H, qd, J=12, 2 Hz), 2.569(2H, t, J=6.4Hz), 3.04-3.23(6H, m), 3.57(2H, d, J=11.6 Hz), 3.66(3H, s),3.93-4.03(1H, m), 6.14(1H, dd, J=8, 1.6 Hz), 6.32(1H, d, J=1.6 Hz),6.79(1H, d, J=7.6 Hz), 7.16(2H, t, J=9.2 Hz), 7.32(2H, dd, J=8.8, 5.6Hz), 11.05-11.20(1H, br-s).

MS: 369(M+H)+.

Example 269:1-[1-(4-Cyanopropyl)piperidin-4-yl]-7-methoxy-1,2,3,4-tetrahydroquinolinehydrochloride

(Yield: 55%).

m.p.: 180-183° C. (decomp.).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.71-1.82(4H, m), 1.97-2.12(2H, m), 2.15-2.28(2H, m), 2.56(2H, t,J=6.4 Hz), 2.67(2H, t, J=7.2 Hz), 2.99-3.18(6H, m), 3.51(2H, br-d,J=11.6 Hz), 3.66(3H, s), 3.90-4.01(1H, m), 6.12(1H, dd, J=8.4, 1.0 Hz),6.29(1H, d, J=1.0 Hz), 6.78(1H, d, J=8.4 Hz), 10.94-11.12(1H, br-s).

MS: 314(M+H)+.

Example 270:1-{1-[2-(2-Thienyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinolinehydrochloride

(Yield: 35%).

m.p.: 232-235° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.73-1.84(4H, m), 2.16-2.29(2H, m), 2.57(2H, t, J=6.4 Hz),3.10(2H, t, J=5.2 Hz), 3.13-3.40(6H, m), 3.58(2H, br-d), 3.66(3H, s),3.91-4.02(1H, m), 6.15(1H, br-d), 6.32(1H, br-s), 6.80(1H, d, J=8.0 Hz),6.97(1H, d, J=1.6 Hz), 6.99(1H, d, J=5.2 Hz), 7.40(1H, dd, J=5.2, 1.6Hz), 11.21-11.33(1H, br-s).

MS: 357(M+H)+.

Example 271:1-{1-[2-(4-Fluorophenyl)ethyl]piperidin-4-yl}-7,8-dimethoxy-1,2,3,4-tetrahydroquinolinehydrochloride

(Yield: 82%).

m.p.: 213-215° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.62-1.89(4H, m), 2.11-2.31(2H, m), 2.57-2.69(2H, m),2.88-3.23(8H, m), 3.51-3.69(2H, m), 3.62(3H, s), 3.71(3H, s),6.40-6.62(1H, br-d), 6.63-6.75(1H, br-d), 7.15(2H, t, J=8.8 Hz),7.29(2H, dd, J=7.6, 5.2 Hz), 10.50-10.77(1H, br-s).

MS: 399(M+H)+.

Example 272:1-{1-[2-(4-Fluorophenyl)ethyllpiperidin-4-yl}-7,8-methylenedioxy-1,2,3,4-tetrahydroquinolinehydrochloride

(Yield: 55%).

m.p.: 225-227° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.71-1.83(4H, m), 2.24(2H, qd, J=12.4, 3.2 Hz), 2.58(2H, t, J=6.0Hz), 2.92-3.10(6H, m), 3.18-3.25(2H, m), 3.58(2H, br-d), 4.14-4.23(1H,m), 5.83(2H, s), 6.23(1H, d, J=8.0 Hz), 6.46(1H, d, J=8.0 Hz), 7.16(2H,t, J=8.8 Hz), 7.29(2H, dd, J=8.8, 5.6 Hz), 10.84-10.91(1H, m).

MS: 383(M+H)+.

Example 273:1-{1-[2-(4-Fluorophenyl)ethyl]piperidin-4-yl}-7-methoxy-8-methyl-1,2,3,4-tetrahydroquinolineoxalate

(Yield: 68%).

m.p.: 176-178° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.66-1.75(4H, m), 1.97-2.09(2H, m), 2.02(3H, s), 2.58(2H, t,J=6.8 Hz), 2.79-3.22(9H, m), 3.40-3.51(2H, m), 3.71(3H, s), 6.47(1H, d,J=8.4 Hz), 6.76(1H, d, J=8.4 Hz), 7.13(2H, t, J=8.8 Hz), 7.29(2H, dd,J=11.2, 8.8 Hz).

MS: 383(M+H)+.

Example 274:1-{1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroauinolinehydrochloride

(Yield: 60%).

m.p.: 153-155° C. (decomp.)

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.70-1.83(4H, m), 2.15-2.29(2H, m), 2.54(2H, t, J=6.4 Hz),3.08(2H, t, J=6.0 Hz), 3.17-3.32(2H, m), 3.56(2H, br-d, J=12.0 Hz), 3.62(3H, s), 3.92-4.03 (1H, m), 4.98 (2H, d, J=4.4 Hz) 6.11 (H, dd, J=7.2,1.0 Hz), 6.32 (1H, d, J=1.0 Hz), 6.76 (1H, d, J=7.2 Hz), 7.41(2H, t,J=8.8 Hz), 8.04(2H, dd, J=8.8, 5.6 Hz), 10.22-10.39(1H, m).

MS: 383(M+H)+.

Example 275:1-{1-[2-(4-Fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinolineoxalate

Sodium borohydride (73 mg) was added at 0° C. to a solution of1-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline(400 mg) in methanol (10 ml). The resultant mixture was stirred at thesame temperature for 1 hr and then at room temperature for 1 hr. Afterthe completion of the reaction, water was added to the reaction solutionfollowed by extraction with ethyl acetate. The resulting residue waspurified by column chromatography (hexane/ethyl acetate system) to give1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinolineas an oil. This product was dissolved in ethanol and oxalic acid wasadded thereto. The resulting precipitate of salt was recrystallized formethanol/ether to give the title compound (280 mg) (yield: 68%).

m.p.: 170-172° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.62-2.01(6H, m), 2.55(2H, t, J=6.4 Hz), 2.58-2.90(4H, m),3.09(2H, t, J=5.6 Hz), 3.21-3.39(2H, m), 3.64(3H, s), 3.65-3.78(1H, m),4.82-4.91(1H, m), 6.06(1H, dd, J=8.4, 2.4 Hz), 6.20(1H, d, J=2.4 Hz),6.75(1H, d, J=8.4 Hz), 7.17(2H, t, J=8.8 Hz), 7.42(2H, dd, J=8.8, 6.0Hz).

MS: 385(M+H)+.

Example 276:1-{1-[2-(4-Fluorophenyl)-2-fluoroethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroguinolinehydrochloride

A solution of1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline(250 mg) in methylene chloride (5 ml) was cooled to −78° C. anddiethylaminosulfur trifluoride (DAST, 0.1 ml) was added thereto. Thenthe reaction solution was stirred at the same temperature for 45 min.After the completion of the reaction, saturated sodium bicarbonate wasadded to the reaction solution, which was then allowed to warm to roomtemperature under stirring. The reaction solution was extracted withethyl acetate and the organic layer was dried over magnesium sulfate.After evaporating the solvent, the resulting residue was purified bysilica gel column chromatography (hexane/hexane system) to give1-{1-[2-(4-fluorophenyl)-2-fluoroethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinolineas an oil. This product was dissolved in ethyl acetate. After addinghydrochloric acid, the resulting salt was recrystallized fromethanol/ether to give the title compound (60 mg) (yield: 24%).

m.p.; 227-229° C.

m.p.: 227-229 C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.72-1.88(4H, m), 2.10-2.34(2H, m), 2.57(2H, t, J=6.0 Hz),3.11(2H, t, J=5.2 Hz), 3.17-3.80(6H, m), 3.66(3H, s), 3.93-4.03(1H, m),6.13(1H, dd, J=8.0 Hz), 6.31(1H, dd, J=50, 8.6 Hz), 6.32(1H, s),6.79(1H, d, J=8.0 Hz), 7.31(2H, t, J=8.8, 6.0 Hz), 7.53(2H, dd, J=8, 5.6Hz), 11.46-11.72(1H, m).

MS: 387(M+H)+.

Example 277-Synthesis of1-[2-(4-fluorophenyl)ethyl]-4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin

(277-1 ) 4-(1-Hydroxy-6-1,2,3,4-tetrahydronaphthalen-1-yl)pyridine

4-Bromopyridine hydrochloride 7.04g (1.0 equivalent) was partitionedbetween an aqueous solution of sodium hydroxide and diethyl ether. Theorganic layer was separated and dried over magnesium sulfate. Undernitrogen atmosphere, this solution was cooled to −78° C. Then a 1.6 Msolution (25.0 ml, 1.0 equivalent) of n-butyllithium in hexane was addeddropwise thereinto and the resultant mixture was stirred for additional30 mm. Next, 6-methoxytetralone (7.049 g, 4.0 mmol) dissolved intetrahydrofuran (50 ml) was added thereto and the resultant mixture wasgradually warmed to room temperature while stirring continuously. Afteradding a saturated aqueous solution of ammonium chloride, the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine and dried over magnesium sulfate. After evaporating the solventunder reduced pressure, the residue was reprecipatated fromchloroform/n-hexane to give the title compound (4.019 g) as a paleyellowish brown powder (yield: 39.4%).

δ(ppm) 1.58-1.68(1H, m), 1.91-2.00(3H, m), 2.81(2H, br-s), 3.72(3H, s),5.69(1H, s), 6.65-6.70(2H, m), 6.77(1H, d, J=8.8 Hz), 7.22(2H, d, J=6.0Hz), 8.45(2H, d, J =6.0 Hz).(277-2)1-[2-(4-Fluorophenyl)ethyl]-4-(6-methoxy-3,4-dihydronaphthalen-1-yl)pyridiniumbromide

Under a nitrogen atmosphere, a mixture of4-(1-hydroxy-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyridine(compound 1-1) (3.978 g, 15.6 mmol), 4-fluorophenethyl bromide (3.322 g,1.05 equivalents) and acetonitrile (100 ml) was stirred at 80° C. for 26hr. Then 6.327 g (2.0 equivalents) of 4-fluorophenethyl bromide wasfurther added thereto and the resultant mixture was stirred foradditional 12 hr. After adding ethyl acetate and water, an insolubleprecipitate was collected by filtration and air-dried at 50° C. to givethe title compound (5.785 g) as a pale brown powder (yield: 84.3%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 2.42-2.47(2H, m), 2.79(2H, br-t), 3.28(2H, br-t), 3.79(3H, s),4.83(2H, t, J=7.4 Hz), 6.54(1H, t, J=4.8 Hz), 6.78(1H, dd, J=2.8, 8.4Hz), 6.86(1H, d, J=8.4 Hz), 6.90(1H, d, J=2.8 Hz), 7.15-7.20(2H, m),7.30-7.33(2H, m), 8.06(2H, d, J=6.8 Hz), 8.96(2H, d, J=6.8 Hz).(277-3)1-[2-(4-Fluorophenyl)ethyl]-4-(6-methoxy-3,4-dihydronaphthalen-1-yl)-1,2,3,6-tetrahydropyridine

1-[2-(4-Fluorophenyl)ethyl]-4-(6-methoxy-3,4-dihydronaphthalen-1-yl)pyridiniumbromide (compound 1-2) (5.710 g, 13 mmol) was dissolved inmethanol (50ml) and stirred under ice cooling. After adding 0.49 g of sodiumborohydride thereto, the resultant mixture was stirred at roomtemperature for 2 hr. After removing the solvent under reduced pressure,water was added to the residue followed by extraction with ethylacetate. The organic layer was washed with water and a saturated aqueoussolution of sodium chloride and dried over magnesium sulfate. Afterevaporating the solvent under reduced pressure, the resulting residuewas purified by silica gel column chromatography (n-hexane/ethyl acetatesystem) to give the title compound (4.169 g) as a pale brown viscous oil(yield: 88.5%).

¹H-NMR (400 MHz, CDCl3):

δ(ppm) 2.21-2.27(2H, m), 2.33-2.38(2H, m), 2.66-2.74(6H, m),2.84-2.88(2H, m), 3.19(2H, br-q), 3.80(1H, s), 5.71(1H, br-quintet),5.84(1H, t, J=4.8 Hz), 6.69(1H, dd, J=2.4, 8.4 Hz), 6.73(1H, d, J=2.4Hz), 6.96-7.00(2H, m), 7.11(1H, d, J=8.4 Hz), 7.17-7.20(2H, m).(277-4)1-[2-(4-Fluorophenyl)ethyl]-4-(6-methoxy-1,2,3,4-tetrahydrofuran-1-yl)piperidine

1-[2-(4-Fluorophenyl)ethyl]-4-(6-methoxy-3,4-dihydronaphthalen-1-yl)-1,2,3,6-tetrahydropyridine(compound 1-3) (1.035 g, 2.85 mmol) was dissolved in methanol (100 ml).After adding 10% palladium-carbon (0.11 g), the mixture wascatalytically reduced under atmospheric pressure for 12 hr. Afterfiltering off the catalyst, 10% palladium-carbon (0.11 g) was addedthereto again and catalytic reduction was carried out under atmosphericpressure for 6 hr. Then the catalyst was filtered off and the solventwas removed under reduced pressure to give the title compound (0.910 g)as a pale brown amorphous solid (yield: 93.9%).

This product was converted into a hydrochloride in a conventional mannerfollowed by recrystallization from ethanol/diisopropyl ether to give thetitle compound as a colorless powder.

Free:

m.p.: 190-191° C. (decomp.).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.58-1.90(8H, m), 2.27(2H, br-s), 2.66-2.64(4H, m), 2.84(2H,br-s), 3.01(2H, br-s), 3.33(2H, br-s), 3.77(3H, s), 6.62(1H, d, J=2.8Hz), 6.68(1H, dd, J=2.8, 8.4 Hz), 6.96-6.70(2H, m), 7.03(1H, d, J=8.4Hz), 7.16-7.20(2H, m).

FAB-MS: [M+H]+: m/z=368.

Example 278: Synthesis of1-[2-(4-fluorophenyl)ethyl]-4-]6-(2-hydroxy)ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]piperidine

(278-1)1-[2-(4-Fluorophenyl)ethyl]-4-[6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]piperidine

47% hydrobromic acid (45 ml) was added to1-[2-(4-fluorophenyl)ethyl]-4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine(2.718 g, 7.57 mmol) and the resultant mixture was heated under refluxfor 1 hr. After adding glacial acetic acid (20 ml), the resultantmixture was heated under reflux for additional 1.5 hr. Then the mixturewas allowed to cool followed by addition of water thereto. The resultingprecipitate was collected by filtration, chloroform and a saturatedaqueous solution of sodium bicarbonate were added thereto and the layerswere separated. The resulting solution was dried over magnesium sulfateand the solvent was evaporated under reduced pressure to give the titlecompound (2.043 g) as a brown amorphous substance (yield: 76.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.35-2.04(10H, m), 2.52-2.70(6H, m), 2.77-2.82(2H, m), 3.08(2H,br-t), 6.45(1H, d, J=2.8 Hz), 6.59(1H, dd, J=2.8, 8.0 Hz), 6.93-6.97(2H,m), 7.00(1H, d, J=8.0 Hz), 7.11-7.14(2H, m).(278-2)1-[2-(4-Fluorophenyl)ethyl]-4-[6-(2-t-butyldimethylsilyloxy)ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]piperidine

55% sodium hydride (0.055 g, 1.1 equivalents) was washed with n-hexaneand suspended in N,N-dimethylformamide (3 ml) followed by stirring underice cooling. To the resultant solution was added1-[2-(4-fluorophenyl)ethyl]-4-[6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]piperidine(compound 2-1) (2.718 g, 7.57 mmol) dissolved in N,N-dimethylformamide(1 ml) and the resultant mixture was stirred at room temperature for 30min. Then the resultant mixture was ice cooled again followed byaddition of (2-t-butyldimethylsilyloxy)ethanol (0.410 g, 1.5equivalents) dissolved in N,N-dimethylformamide (1 ml). Under a nitrogenatmosphere, the resulting mixture was stirred at 50° C. for 25 hr. Afteradding water, the reaction solution was extracted with ethyl acetate.The extract was washed successively with water and brine and dried overmagnesium sulfate. After removing the solvent under reduced pressure,the resulting residue was purified by silica gel column chromatography(n-hexane/ethyl acetate system) to give the title compound (0.371 g) asa colorless viscous oil (yield: 63.4%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.10(6H, s), 0.91(9H, s), 1.36-1.98(12H, m), 2.40-2.54(2H, m),2.60-2.79(4H, m), 2.99-3.06(2H, m), 3.93-3.96(2H, m), 3.98-4.01(2H, m),6.61(1H, d, J=2.4 Hz), 6.68(1H, dd, J=2.4, 8.4 Hz), 6.93-6.97(2H, m),7.04(1H, d, J=8.4 Hz), 7.12-7.16(2H, m).(278-3)1-[2-(4-Fluorophenyl)ethyl]-4-[6-(2-hydroxy)-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]piperidine

1-[2-(4-Fluorophenyl)ethyl]-4-[6-(2-t-butyldimethylsilyloxy)ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]piperidine(compound 2-2) (0.350 g, 0.684 mmol) was dissolved in tetrahydrofuran (5ml). After adding a 1.0 M solution (821 ml, 1.2 equivalents) oftetra-n-butylammonium fluoride in tetrahydrofuran thereto, the resultantmixture was stirred at room temperature for 9.5 hr. After adding water,the reaction solution was extracted with ethyl acetate. The extract waswashed successively with water (for three times) and brine and driedover magnesium sulfate. After evaporating the solvent, the resultingresidue was purified by silica gel column chromatography(chloroform/methanol system) to give the title compound (0.242 g) as acolorless viscous oil (yield: 89.0%).

This product was converted into a hydrochloride in a conventional mannerand recrystallized from ethanol/diisopropyl ether to give the titlecompound as a colorless powder.

Free:

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.21-1.88(12H,m), 2.41-2.45(2H,m), 2.51-2.70(4H, m),2.90-2.97(2H, m), 3.83(2H, t, J=9.2 Hz), 3.95(2H, t, J=9.2 Hz), 6.53(1H,d, J=2.8 Hz), 6.60(1H, dd, J=2.8, 8.8 Hz), 6.83-6.87(2H, m), 6.96(1H, d,J=8.8 Hz), 7.02-7.05(2H, m).

FAB-MS: [M+H]+: m/z=398.

m.p.: 213-215° C. (decomp.).

Example 279: Synthesis oftrans-1-(4-ethylpiperazin-1-yl)-7-methoxy-2-(4-trifluoromethylphenoxy)-1,2,3,4-tetrahydronaphthalene

(279-1)trans-1-(4-Ethylpiperazin-1-yl)-2-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalene

7-Methoxy-3,4-dihydronaphthalene-1,2-oxide (5.28 g) synthesized inaccordance with the method described in Tetrahedron, 33, 85-94. wasdissolved in n-butanol (100 ml). After adding ethylpiperazine (3.42 g),the resultant mixture was heated under reflux for 12 hr. After removingthe solvent under reduced pressure, the residue was recrystallized fromethyl acetate (5 ml) and ether (80 ml). The crystals were collected byfiltration and washed with ether to give the title compound (6.88 g) aspale yellow crystals (yield: 79%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.73-1.85(1H, m), 2.09-2.16(1H, m), 2.48(4H, br-s), 2.77(2H, m),2.91(4H, br-s), 3.16(1H, br-s), 3.68(1H, d, J=8.5 Hz), 3.78(3H, s),3.95(1H, ddd, J=3.0 Hz, 8.5 Hz, 10.5 Hz), 6.71(1H, br-d), 6.99(1H, d,J=10.0 Hz), 7.12(1H, br-s).(279-2)trans-1-(4-Ethylpiperazin-1-yl)-7-methoxy-2-(4-trifluoromethylphenoxy)-1,2,3,4-tetrahydronaphthalene

A solution of potassium t-butoxide (247 mg) and 4-fluorobenzotrifluoride(492 mg) in dimethylformamide (1 ml) was added slowly at roomtemperature to a solution oftrans-1-(4-ethylpiperazin-1-yl)-2-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalene(435 mg) in dimethylformamide (3 ml) and the resultant mixture wasstirred for 4 hr. After adding water (50 ml), the reaction mixture wasextracted with ethyl acetate (50 ml) for three times. The organic phasewas washed with water (50 ml) twice and brine (50 ml) once and driedover anhydrous magnesium sulfate followed by concentration under reducedpressure. The resulting residue was purified by silica gel columnchromatography (NH-DM2035, Fuji Silysia Chemical Ltd., hexane/ethylacetate system) to give the title compound (190 mg) as a colorless oil(yield: 29%).

m.p. (oxalate): 207-210° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.03(3H, t, J=7.0 Hz), 1.85-1.96(1H, m), 2.15-2.22(1H, m),2.39(2H, q, J=7.0 Hz), 2.42(4H, br-s), 2.70(2H, br-s), 2.77(2H, br-s),2.80(2H, t, J=6.0 Hz), 3.81(3H, s), 4.05(1H, d, J=7.5 Hz), 4.79(1H, m),6.76(1H, dd, J=3.0 Hz, 8.0 Hz), 6.97(2H, d, J=8.5 Hz), 7.02(1H, d, J=8.0Hz), 7.33(1H, d, J=3.0 Hz), 7.53(2H, d, J=8.5 Hz).

FAB-Mass:435(MH+).

Example 280: Synthesis of1-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-7-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

(280-1) 1-Hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalene

7-Methoxy-1,2,3,4-tetrahydronaphthalen-1-one (5 g) was dissolved inmethanol and sodium tetrahydroborate (1.3 g) was added thereto at 0° C.After reacting at room temperature for 2 hr, the reaction solution waspartitioned between ethyl acetate and water. The ethyl acetate layer waswashed with water, dried and concentrated under reduced pressure to givethe title compound (5.19 g) as a colorless oil.(280-2)1-(4-Acetylpiperazin-1-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene

1-Hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalene (5.19 g) was reactedwith thionyl chloride (4.3 ml) in ether at room temperature for 3 hr.Then the reaction solution was partitioned between ether and water. Theether layer was washed successively with water, a saturated aqueoussolution of sodium bicarbonate and brine, dried and concentrated underreduced pressure. The resulting residue, 1-acetylpiperazine andpotassium carbonate were heated under reflux in acetone for 10 hr. Thenthe reaction solution was filtered and insolubles were washed withmethylene chloride. After concentrating the filtrate under reducedpressure, the resulting residue was purified by silica gel columnchromatography (methylene chloride/methanol system) to give the titlecompound (3.0 g) as a pale yellow oil.(280-3) 7-Methoxy-1-(Diperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

1-(4-Acetylpiperazin-1-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene (0.85g) was dis solved in ethanol (10 ml). After adding an 8 N aqueoussolution (3 ml) of sodium hydroxide, the resultant mixture was heatedunder reflux for 3 hr. Then the liquid reaction mixture was concentratedunder reduced pressure and the residue was purified by NH-silica gelcolumn chromatography (ethyl acetate) to give the title compound (0.6 g)as a pale brown oil.(280-4)1-[4-(4-Fluorophenylacetyl)piperazin-1-yl]-7-methoxy-1,2,3,4-tetrahydronaphthalene

7-Methoxy-1-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (0.6 g) wasreacted in methylene chloride for 2 hr with an acid chloride preparedfrom 4-fluorophenylacetic acid (0.44 g) and thionyl chloride (0.21 ml)Then the liquid reaction mixture was partitioned between methylenechloride and water, extracted with methylene chloride, dried andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (toluene/acetone system) to give thetitle compound (0.56 g) as an oil.(280-5)1-{4-[2-(4-Fluorophenyl)ethyl]piperdin-1-yl}-7-methoxy-1,2,3,4-tetrahydronaphthalene

1-[4-(4-Fluorophenylacetyl)piperazin-1-yl]-7-methoxy-1,2,3,4-tetrahydronaphthalene(0.41 g) and lithium aluminum hydride (0.05 g) were heated under refluxin THF (15 ml) for 6 hr. Next, the reaction solution was cooled andwater (50 ml) a 5 N aqueous solution (50 ml) of sodium hydroxide andfurther water (150 ml) were successively added thereto. After stirringthe resultant mixture at room temperature for 1 hr, the resultingprecipitate was filtered through celite and washed with THF. Thefiltrate was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography(toluene/acetone system) to give the title compound (0.38 g) as an oil.

m.p.: 205° C. (decomp.).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.60-1.70(2H, m), 1.93-2.02(2H, m), 2.48-2.81(14H, m),3.76-3.83(1H, m), 3.79(3H, s), 6.71(1H, dd, J=8.4, 2.8 Hz), 6.96(2H, t,J=8.4 Hz), 7.12-7.19(3H, m), 7.32(1H, d, J=2.8 Hz).

FAB-Mass: 269(MH+).

Example 281: Synthesis of1-{4-[2-(4-fluorophenyl)-2-oxoethyl]piperazin-1-yl}-7-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

7-Methoxy-1-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (0.27 g),4-fluorophenacyl bromide (0.24 g) and diisopropylethylamine (0.43 g)were dissolved in DMF (15 ml) and reacted at room temperature for 12 hr.Then the liquid reaction mixture was distributed between ethyl acetateand water. The ethyl acetate layer was washed with water, dried andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (ethyl acetate/n-hexane system) togive an oil (0.34 g). This product was converted into a hydrochloride ina conventional manner to give the title compound as a white powder.

m.p.: 194° C. (decomp.).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.60-1.69(2H, m), 1.92-2.01(2H, m), 2.53-2.68(8H, m), 3.76(2H,s), 3.79(3H, s), 6.70(1H, dd, J=8.4, 2.8 Hz), 6.97(1H, d, J=8.4 Hz),7.09-7.15(2H, m), 7.31(1H, d, J=2.8 Hz), 8.04-8.10(2H, m).

FAB-Mass: 383(MH+).

Example 282-1: Synthesis of 8-aminobenzosuberone

Ammonium nitrate (24 g) was added in portions at −10° C. to a solutionof benzosuberone (40 g) and trifluoroacetic anhydride (85 ml) inchloroform (400 ml) and the resultant mixture was stirred at roomtemperature overnight. The reaction solution was concentrated underreduced pressure, then a saturated aqueous solution of sodiumbicarbonate and ethyl acetate were added thereto and the layers wereseparated. The organic layer was washed with brine and dried overanhydrous magnesium sulfate followed by purifying by silica gel columnchromatography (hexane/ethyl acetate system). Then palladium carbon (5g) and ethanol (300 ml) were added thereto and catalytic reduction wascarried out under hydrogen atmosphere at 50° C. After stirringovernight, the catalyst was filtered off and the residue wasconcentrated under reduced pressure and purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(10 g) (yield: 24%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.71-1.89(4H, m), 2.67-2.72(2H, m), 2.80-2.85(2H, m), 3.70(2H,br-s), 6.76(1H, dd, J=8, 3 Hz), 6.97(1H, d, J=8 Hz), 7.04(1H, t, J=3Hz).Example 282-2: Synthesis of 8-methoxybenzosuberone

An aqueous solution (15 ml) of sodium nitrite (9.0 g) was added dropwiseinto a mixture of 8-aminobenzosuberone (4.0 g), conc. sulfuric acid (3ml) and water (47 ml) at 5° C. or below. After 30 min, the reactionsolution was added dropwise into a saturated aqueous solution (25 ml) ofcopper sulfate heated to 90° C. and stirred for 30 min. After coolingthe reaction solution to room temperature, ethyl acetate was addedthereto and the layers were separated. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. To the residue were added methyl iodide, potassiumcarbonate and dimethylformamide and the resultant mixture was stirred atroom temperature for 7 hr. After concentrating the reaction solutionunder reduced pressure, water and ethyl acetate were added thereto andthe layers were separated. The organic layer was washed with brine anddried over anhydrous magnesium sulfate followed by purifying by silicagel column chromatography (hexane/ethyl acetate system) to give thetitle compound (3.5 g) (yield: 80%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.78-1.90(4H, m), 2.70-2.75(2H, m), 2.87-2.92(2H, m), 3.81(3H,s), 6.99(1H, dd, J=8, 3 Hz), 7.11(1H, d, J=8 Hz), 7.29(1H, t, J=3 Hz).Example 282-3: Synthesis of1-(4-fluorophenethyl)-4-(2-methoxybenzocycloheptan-9-yl)piperazine

Sodium borohydride (0.7 g) was added to a solution of8-methoxybenzosuberone (3.5 g) in ethanol (40 ml) and the resultantmixture was stirred at room temperature for 1 hr. Then the reactionsolution was concentrated under reduced pressure and diluted with asaturated aqueous solution of sodium bicarbonate and ethyl acetate andthe layers were separated. The organic layer was washed with brine anddried over magnesium sulfate. After evaporating the solvent, toluene (50ml) and thionyl chloride (2.4 g) were added to the residue. Theresultant mixture was stirred for 2 hr and then concentrated underreduced pressure. To the residue were added dimethylformamide (50 ml),1-(4-fluorophenethyl)piperazine (2.1 g) synthesized in accordance withthe method described in JP-A 54-92979 and triethylamine (0.7 g) and theresultant mixture was stirred at 100° C. for 3 hr. After concentratingthe liquid reaction mixture under reduced pressure, a saturated aqueoussolution of sodium bicarbonate and ethyl acetate were added thereto andthe layers were separated. The organic layer was washed with brine anddried over anhydrous magnesium sulfate. The resulting residue waspurified by silica gel column chromatography (methylene chloride/ethanolsystem) followed by conversion into a hydrochloride in a conventionalmanner to give the hydrochloride (230 mg) of the title compound as awhite powder (yield: 11%).

m.p (hydrochloride): 188-190° C.

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.20-1.35(1H, m), 1.50-1.65(2H, m), 1.74-1.98(4H, m),2.06-2.19(2H, m), 2.21-2.67(4H, m), 2.96-3.06(3H, m), 3.20-3.35(3H, m),3.49-3.80(2H, m), 3.74(3H, s), 6.69-6.89(2H, m), 7.00-7.09(1H, m),7.12-7.20(2H, m), 7.28-7.40(2H, m).

FAB-Mass: 383(MH+).

Example 283: Synthesis of5-{4-[2-(4-fluorophenyl)-ethyl]piperazin-1-yl}-5,6,7,8-tetrahydroisoquinolinehydrochloride

(283-1) 5,6,7,8-Tetrahydroisoquinoline-2-oxide

5,6,7,8-Tetrahydroisoquinoline (10 g) was added to methylene chloride(100 ml) and a 10% aqueous solution (100 ml) of sodium carbonate. Undervigorous stirring, a 70% solution of m-chloroperbenzoic acid (20 g) inmethylene chloride (100 ml) was dropped thereinto at 0° C. Then thereaction solution was extracted with methylene chloride. The methylenechloride layer was washed with brine, dried and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (methylene chloride/methanol system) to give thetitle compound (7.50 g) as a colorless oil.(283-2) 5,6,7,8-Tetrahydroisoquinolin-5-ol

5,6,7,8-Tetrahydroisoquinoline-2-oxide (7.50 g) was dissolved in aceticanhydride (30 ml). After reacting at 120° C. for 6 hr, the reactionsolution was concentrated under reduced pressure. Next, a 10% aqueoussolution (30 ml) of hydrochloric acid was added to the residue followedby heating at 100° C. for 2 hr. The reaction solution was cooled,basified with 5N sodium hydroxide and extracted with ethyl acetate. Theethyl acetate layer was washed with water and dried. After evaporatingthe solvent under reduced pressure, the resulting residue was purifiedby silica gel column chromatography (ethyl acetate) to give the titlecompound (1.90 g).(283-3)5-{4-[2-(4-Fluorophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydroisoquinolinehydrochloride

5,6,7,8-Tetrahydroisoquinolin-5-ol (1.90 g), methanesulfonyl chloride(1.48 g) and triethylamine (5.0 ml) were reacted in THF (50 ml) at 0° C.for 6 hr. The reaction solution was partitioned between ethyl acetateand a saturated aqueous solution of sodium bicarbonate. The ethylacetate layer was washed with water, dried and concentrated underreduced pressure to give a pale yellow oil. This product was dissolvedin DMF followed by addition of 4-[2-(4-fluorophenyl)ethyl]piperazine(2.0 g) and potassium carbonate (2.0 g). After reacting for 12 hr, thereaction solution was concentrated under reduced pressure and theobtained residue was purified by silica gel column chromatography(methylene chloride/methanol system) to give a pale yellow oil (0.71 g).Next, this product was converted into a hydrochloride in a conventionalmanner to give the title compound (0.52 g) as a white powder.

m.p.: 174-176° C.

¹H-NMR (400 MHz, D₂O)

δ(ppm) 1.77(2H, m), 1.99-2.16(2H, m), 2.87(2H, m), 3.03(4H, m), 3.38(4H,m), 4.19(1H, m), 7.05(2H, t, J=8.4 Hz), 7.26(2H, dd, J=8.4, 7.2 Hz),8.28(1H, d, J=8.0 Hz), 8.43(1H, d, J=8.0 Hz), 8.45(1H, s).

FAB-Mass: 340(MH+).

Example 284: Synthesis of1-[1-(4-fluorophenethyl)pieridin-4-yl]-5,6-methylenedioxyindoline

1-(4-Fluorophenethyl)-4-(3,4-methylenedioxyphenyl)-aminopiperidine (10g) synthesized in accordance with the method described in ReferentialExample 1 of JP-B 40-6347 was treated as in Example 106 to give thehydrochloride (330 mg) of the title compound as dark red prismaticcrystals (yield: 2.8%).

m.p. (hydrochloride): 229° C. (decomp.)

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.80-2.09(4H, m), 2.72-2.85(2H, m), 2.99-3.19(4H, m),3.19-3.35(4H, m), 3.55-3.61(3H, m), 5.82(2H, s), 6.44(1H, s), 6.71(1H,s), 7.12-7.20(2H, m), 7.29-7.38(2H, m).

FAB-Mass: 369(MH+).

Example 285: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline (7.5g) obtained in Example 133 was dissolved in acetone (500 ml) at 50° C.To the resultant solution was added active manganese dioxide (35.6 g) inportions under stirring. The resulting suspension was heated underreflux for 1.5 hr, then filtered through celite and washed with acetone.The filtrate was concentrated under reduced pressure and the resultingpale yellow solid was recrystallized from ethyl acetate to give thetitle compound (4.2 g) as awhite powder (yield: 56%).

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.86(s, 3H), 1.88-2.04(m, 4H), 2.23(dt, J=11.2, 2.4 Hz, 2H),2.55-2.62(m, 2H), 2.74-2.81(m, 2H), 3.09(br-d, 2H), 4.26-4.36(m, 1H),4.33(d, J=5.6 Hz, 2H), 6.41(d, J=3.2 Hz, 1H), 6.94(d, J=7.2 Hz, 1H),7.08-7.15(m, 2H), 7.26-7.33(m, 2H), 7.41(br-s, 1H), 7.45-7.49(m, 2H),8.26-8.32(m, 1H).

m.p.: 127-128° C.

Mass: FAB+394(M+H).

Example 286: Synthesis of1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-(N-isopropylcarbamoylmethyl)indole

A suspension of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(isopropylcarbamoylmethyl)indoline(1 g) obtained in Example 151 and active manganese dioxide (4 g) in1,2-dichloroethane (100 ml) was heated under reflux for 1.5 hr, thenfiltered through celite and concentrated under reduced pressure. Theresulting pale yellow solid was recrystallized from ethyl acetate togive the title compound (0.4 g) as a white powder (yield: 40%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.04(d, J=6.0 Hz, 6H), 2.04-2.18(m, 4H), 2.25-2.40(m, 2H),2.63-2.74(m, 2H), 2.80-2.91(m, 2H), 3.15-3.28(m, 2H), 3.68(s, 2H),4.02-4.12(m, 1H), 4.20-4.31(m, 1H), 5.20-5.32(m, 1H), 6.53(d, J=3 Hz,1H), 6.95-7.02(m, 3H), 7.18-7.21(m, 2H), 7.26-7.28(m, 2H), 7.61(d, J=8Hz, 1H).

m.p.: 146-148° C.

Mass: ESI 422(M+).

Example 287: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-methylpyrrol-2-yl)indole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindole (0.2 g) wasdissolved in toluene (2.50 ml). Next, 1-methyl-2-tributylstannylpyrrole(1.44 g) synthesized in accordance with the method described inTetrahedron Lett., 4407 (1986). with the use of 1-methylpyrrole andtributylthin chloride was added thereto and the resultant mixture washeated under reflux for 3 hr under nitrogen atmosphere. After addingethyl acetate, the mixture was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound (0.115 g) as a yellow oil(yield: 57.28%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.92-1.99(4H, m), 2.05-2.13(2H, m), 2.47-2.51(2H, m),2.64-2.68(2H, m), 3.32(2H, br-d), 3.50(3H, s) 4.05-4.13(1H, m),6.16-6.19(2H, m), 6.38(1H, d, J=3.6 Hz), 6.57(1H, t, J=2.2 Hz), 6.82(2H,t, J=8.6 Hz), 6.98-7.03(3H, m), 7.11(1H, d, J=3.6 Hz), 7.23(1H, s),7.48(1H, d, J=8.8 Hz).

ESI-Mass: 402.

Example 288: Synthesis of1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indole

A suspension of 1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indoline(0.80 g) obtained in Example 36 and active manganese dioxide (1.32 g) inchloroform (30 ml) was heated under reflux for 6 hr with vigorousstirring. Then the reaction mixtures were filtered through celite andthe residue was washed with chloroform. The filtrate was concentratedunder reduced pressure and the obtained residue was crystallized from asolvent mixture of ethyl acetate with hexane to give the title compound(0.64 g) as a white powder (yield: 80.4%).

m.p.: 133-134° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.02(3H, s), 2.06-2.35(5H, m), 2.64-2.73(2H, m), 2.82-2.90(2H,m), 3.15-3.25(2H, br-d), 4.22-4.32(1H, m), 4.41(2H, d, J=5.6 Hz),6.53(1H, d, J=3.6 Hz), 7.07-7.13(1H, m), 7.18-7.26(5H, m), 7.38(1H, d,J=8.0 Hz), 7.63(2H, d, J=8.0 Hz).

FAB-Mass: 376(MH+).

Example 289: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanoindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-cyanoindoline (0.50 g)obtained in Example 124 and active manganese dioxide (1.00 g) weretreated as in Example 288 to give the title compound (0.42 g) as a whitepowder (yield: 83.8%).

m.p.: 131-132° C.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.06-2.16(3H, m), 2.25-2.34(2H, m), 2.64-2.70(2H, m),2.79-2.87(2H, m), 3.16-3.24(2H, m), 4.21-4.31(1H, m), 4.41(2H, d, J=5.6Hz), 6.60(1H, d, J=3.2 Hz), 6.97-7.03(2H, m), 7.16-7.22(2H, m), 7.33(1H,dd, J=8.0, 1.2 Hz), 7.44(1H, d, J=3.2 Hz), 7.67(2H, d, J=8.0 Hz),7.73(1H, br-s).

FAB-Mass: 378(MH+).

Example 290: Synthesis ofcis-1-[1-(4-fluorophenethyl)-3-methylpiperidin-4-yl]indole

cis-1-[1-(4-Fluorophenethyl-3-methylpiperidin-4-yl]indoline wassynthesized in a similar manner to the one of Example 79-4 by startingwith indoline (560 mg),1-[2-(4-fluorophenyl)ethyl]-3-methyl-4-piperidone (1.19 mg) and sodiumtriacetoxyborohydride (2.40 g). As the by-product in this reaction, thetitle compound (30 mg) was obtained as awhite amorphous substance(yield: 3%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 0.80(3H, d, J=6.5 Hz), 1.88(1H, br-d), 2.26(1H, dt, J=12.0, 3.5Hz), 2.35-2.67(5H, m), 2.74-2.82(2H, m), 2.89(1H, br-d), 3.14(1H, br-d),4.46(1H, dt, J=120.5, 4.0 Hz), 6.49(1H, d, J=3.1 Hz), 6.98(2H, br-t),7.10(1H, br-d), 7.16-7.22(4H, m), 7.36(2H, d, J=8.0 Hz), 7.64(2H, d,J=8.0 Hz).

FAB-Mass: 337(MH+).

Example 291: Synthesis of1-[1-(4-fluorophenethyl)homopiperidin-4-yl]-6-methoxyindoline

(291-1) 1-(4-Fluorophenethyl)-4-(3-methoxyphenylamino)-homopiperidine

4-Fluorophenylacetic acid (1.5 g) was dissolved in tetrahydrofuran (44ml). To the resultant solution was added N,N-carbonyldimidazole (1.6 g)and the resultant mixture was stirred at room temperature for 15 min.Next, 4-homopiperidone hydrochloride (1.0 g) synthesized in accordancewith the method described in Synth. Commun., 1249(1992). andtriethylamine (1.2 ml) were successively added thereto followed bystirring at room temperature for 12 hr. After adding water, the reactionsolution was partitioned between water and ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran and lithium aluminum hydride was added thereto under icecooling. Next, the resultant mixture was heated under reflux and treatedin a conventional manner. The resulting product was purified by silicagel column chromatography (hexane/ethyl acetate system) to give a brownoil.

The above product and m-anisidine (0.39 ml) were treated as in Example 1to give a yellow oil. This product was dissolved in tetrahydrofuran (30ml). Under ice cooling, lithium aluminum hydride (0.72 g) was addedthereto and the resultant mixture was heated under reflux for 2.5 hr.Under ice cooling, water (0.72 ml), a 5 N aqueous solution (0.72 ml) ofsodium hydroxide and further water (2.2 ml) were successively addedthereto and the resulting solid was filtered off. The filtrate wasconcentrated under reduced pressure and the obtained residue waspurified by silica gel column chromatography (ethyl acetate/methanolsystem) to give the title compound (1.348 g) as a brown oil (yield:44.6%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.62-1.79(5H, m), 1.95-2.04(1H, m), 2.59-2.67(2H, m),2.70-2.85(6H, m), 3.66(1H, m), 3.76(3H, s), 4.02(1H, br-s), 6.00(1H, t,J=2.4 Hz), 6.12(1H, ddd, J=0.8, 2.4, 8.0 Hz), 6.23(1H, ddd, J=0.8, 2.4,8.0 Hz), 6.98(2H, t, J=8.8 Hz), 7.05(1H, t, J=8.0 Hz), 7.16(2H, dd,J=4.2, 8.8 Hz).(291-2) 1-(4-Fluorophenethyl)-4-(6-methoxyisatin-1-yl)homopiperidine

1-(4-Fluorophenethyl)-4-(3-methoxyphenylamino)homopiperidine (1.148 g)was treated in accordance with the method described in J. Prakt. Chem.,137 (1922). to give the title compound (1.203 g) as an orange oil(yield: 90.6%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.83-2.00(3H, m), 2.10(2H, m), 2.78(7H, br-s), 2.87(2H, br-s),3.93(3H, s), 3.43(1H, m), 4.40(1H, br-s), 6.52(1H, s), 6.53(1H, d, J=8.8Hz), 6.99(1H, t, J=8.8 Hz), 7.18(1H, dd, J=5.6, 8.8 Hz), 7.59(1H, d,J=8.8 Hz).(291-3) 1-[1-(4-Fluorophenethyl)homopiperidin-4-yl]-6-methoxyindoline

1-(4-Fluorophenethyl)-4-(6-methoxyisatin-1-yl)homopiperidine (0.4 g) wasdissolved in tetrahydrofuran (1.0 ml). Under nitrogen atmosphere, a 2.0M solution (4.0 ml) of borane-tetrahydrofuran complex in tetrahydrofuranwas added dropwise thereinto in a water bath followed by heating underreflux for 3 hr. The reaction solution was ice cooled and water wasadded thereto. Next, the reaction solution was partitioned between waterand ethyl acetate and the organic layer was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was dissolved in pyridine (5.0 ml) and stirred atroom temperature for 11 hr. After adding water, the reaction solutionwas partitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Then the resulting residue waspurified by NH-silica gel column chromatography (hexane/ethyl acetatesystem) to give1-(4-florophenethyl)-4-(6-methoxyindol-1-yl)homopiperidine as a yellowoil. Then this product was treated as in Production Example 64 to givethe free title compound (0.095g) asayellowoil (yield: 27.2%).

Next, this product was treated with oxalic acid in a conventional mannerto give the oxalate of the title compound as a hygroscopic solid.

Free:

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.61-1.99(6H, m), 2.66-2.90(10H, m), 3.38(2H, dt, J=1.6, 8.6 Hz),3.63(1H, m), 3.76(3H, s), 6.00(1H, d, J=2.4 Hz), 6.12(1H, dd, J=2.4, 7.6Hz), 6.92(1H, d, J=7.6 Hz), 6.97(2H, t, J=8.4 Hz), 7.15(2H, dd, J=5.6,8.4 Hz).

ESI-Mass: 369.1

Example 292: Synthesis of1-[1-(4-fluorophenethyl)-pyrrolidin-3-yl]-6-methoxyindoline

(292-1) 1-Benzyl-3-(6-methoxyindolin-1-yl)pyrrolidine

1-Benzyl-3-pyrrolidone (10.0 g) and m-anisidine (0.39 ml) were treatedas in Example 1 to give a brown oil. Then this product was treated as inthe above (291-2) to give red crystals. Subsequently, these crystalswere treated as in the above (291-3) to give the title compound (2.301g) as a pale yellow oil (yield: 13.1%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 2.00(1H, br-s), 2.21(1H, br-s), 2.68-2.98(4H, br-s), 2.86 (1H, t,J=8.0 Hz), 3.42 (1H, q, J=8.0 Hz), 3.60-3.90 (2H, br-s), 3.75(3H, s),4.24(1H, br-s), 6.09(1H, d, J=2.4 Hz), 6.16(1H, dd, J=2.4, 8.0 Hz),6.92(1H, d, J=8.0 Hz), 7.27-7.42(5H, m).(292-2) 1-[1-(4-Fluorophenethyl)pyrrolidin-3-yl]-6-methoxyindoline

1-Benzyl-3-(6-methoxyindolin-1-yl)pyrrolidine (0.5 g) was treated as inTetrahedron Lett., 1567 (1977). to give a yellow oil. Then this productand 4-fluorophenethyl bromide (0.15 g) were treated as in Example 2 togive the free title compound (2.301 g) as a pale yellow oil (yield:13.1%).

Next, this free compound was treated with oxalic acid in acetone in aconventional manner to give the oxalate of the title compound as ahygroscopic amorphous solid.

Oxalate:

¹H-NMR (400 MHz, DMSO-d₆):

δ(ppm) 1.89(1H, m), 2.08(1H, m), 2.62-3.06(10H, m), 3.32(2H, t, J=8.2Hz), 3.65(3H, s), 4.30(1H, m), 6.10(1H, dd, J=2.0, 8.0 Hz), 6.15(1H, d,J=2.0 Hz), 6.87(1H, d, J=8.0 Hz), 7.10(2H, t, J=8.4 Hz), 7.27(2H, dd,J=5.4, 8.4 Hz).

ESI-Mass: 341.1.

Example 293: Synthesis of3,3-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline

(293-1) 3,3-Dimethyl-6-bromoindolin-2-one

A solution (50 ml) of 6-bromoindolin-2-one (3.18 g) in THF was cooled to−78° C. and 1.5 M lithium diisopropylamide (20 ml) was added dropwisethereinto followed by stirring for 15 min. After adding methyl iodide(0.92 ml), the reaction mixture was brought to room temperature andstirred for 1 hr. Then the reaction solution was cooled to −78° C. againand 1.5 M lithium diisopropylamide (10 ml) was added dropwise thereintofollowed by stirring for 15 min. After adding methyl iodide (0.92 ml),the reaction solution was brought to room temperature with stirring.Then a saturated aqueous solution of ammonium chloride was added theretoand the resultant mixture was extracted with ethyl acetate. The residuewas washed with hexane to give the title compound (3.35 g) as a whiteamorphous solid (yield: 93.0%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.38(6H, s), 7.05(1H, d, J=8.0 Hz), 7.096(1H, d, J=1.6 Hz),7.169(1H, d, J=1.6 Hz), 8.41(1H, m).(293-2) 3.3-Dimethyl-6-bromoindoline

A borane-dimethylsulfide complex (3 ml) was added dropwise into asolution (80 ml) of 3,3-dimethyl-6-bromoindolin-2-one (3.35 g) intoluene under stirring at 60° C. Then the reaction mixtures were heatedunder reflux for 3 hr. Under ice cooling, a 5 N aqueous solution (20 ml)of sodium hydroxide was added thereto and the resultant mixture wasstirred at room temperature for 30 min. Then the reaction mixtures wereextracted with ethyl acetate, washed with water and brine and dried. Theextract was concentrated under reduced pressure to give the titlecompound (3.10 g) as a yellow oil (yield: 98.3%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.28(6H, s), 3.35(2H, s), 6.83-6.91(3H, m).(293-3)3,3-Dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline

3,3-Dimethyl-6-bromoindoline (3.10 g),1-[2-(4-fluorophenyl)ethyl]-4-piperidone (2.81 g) and triacetoxylatedsodium borohydride (5.70 g) were treated as in Example 16 to give thetitle compound (2.72 g) as a white amorphous solid (yield: 49.8%).

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.24(6H, s), 1.80(4H, br-s), 2.13-2.24(2H, m), 2.58-2.67(2H, m),2.79-2.86(2H, m), 3.11-3.21(2H, m), 3.17(2H, s), 3.28-3.40(1H, m),6.44(1H, s), 6.72(1H, d, J=8.0 Hz), 6.80(1H, d, J=8.0 Hz), 6.93-7.01(2H,m), 7.13-7.20(2H, m).

FAB-Mass: 432(MH+).

Example 294: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(ethylcarbamoylmethyl)indole

A suspension of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(ethylcarbamoylmethyl)indoline(0.41 g) obtained in Example 149 and active manganese dioxide (0.40 g)in chloroform (30 ml) was vigorously stirred at 50° C. for 6 hr. Thenthe reaction mixtures were filtered through celite and the residue waswashed with chloroform. After concentrating the filtrate under reducedpressure, the residue was recrystallized from chloroform/hexane to givethe title compound (0.33 g) as white needles (yield: 89.5%).

m.p.: 159.6-160.1° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.02(3H,t,J=7.2 Hz), 2.07-2.13(4H, m),2.25-2.32(2H, m), 2.64-2.68(2H, m), 2.81-2.85(2H, m), 3.17-3.26(4H, m),3.70(2H,s), 4.21-4.29(1H, m), 5.40(1H, br-t), 6.53(1H, d, J=3.2 Hz),6.95-7.01(3H, m), 7.17-7.21(2H, m), 7.26-7.28(2H, m), 7.61(1H, d, J=8.0Hz).ESI-Mass; 408(MH+).Example 295: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[N-(cyclopropylcarbamoyl)methyl]indole

A suspension of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(cyclopropylcarbamoyl)methyl]indoline(0.04 g) obtained in Example 154 and active manganese dioxide (0.04 g)in chloroform (30 ml) was vigorously stirred at 50° C. for 10 hr. Thenthe reaction mixtures were filtered through celite and the residue waswashed with chloroform. After concentrating the filtrate under reducedpressure, the residue was recrystallized from chloroform/hexane to givethe title compound (0.03 g) as a white powder (yield: 81.9%).

m.p.: 156.4-156.8° C.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 0.34-0.38(2H, m), 0.68-0.73(2H, m),2.06-2.14(4H, m), 2.25-2.32(2H, m), 2.62-2.68(3H, m), 2.81-2.85(2H, m),3.18(2H, br-d), 3.68(2H, s), 4.20-4.28(1H, m), 5.50(1H, br-s), 6.52(1H,d, J=3.2 Hz), 6.93(1H, dd, J=1.4, 8.2 Hz), 6.97-7.01(2H, m),7.17-7.20(2H, m), 7.25-7.27(2H, m), 7.60(1H, d, J=8.2 Hz).ESI-Mass; 420(MH+).Example 296: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[N-(isobutylcarbamoyl)methyl]indole

A suspension of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(isobutylcarbamoyl)methyl]indoline(0.07 g) obtained in Example 152 and active manganese dioxide (0.07 g)in chloroform (30 ml) was vigorously stirred at 50° C. overnight. Thenthe reaction mixtures were filtered through celite and the residue waswashed with chloroform. After concentrating the filtrate under reducedpressure, the residue was recrystallized from chloroform/hexane to givethe title compound (0.05 g) as a white powder (yield: 70.0%).

m.p.: 131.8-132.2° C.

¹H-NMR(40OMHz, CDCl₃); δ(ppm) 0.79(6H, d, J=6.8 Hz), 1.61-1.71(1H, m),2.07-2.13(4H, m), 2.24-2.31(2H, m), 2.64-2.68(2H, m), 2.81-2.85(2H, m),3.01(2H, t, J=6.4 Hz), 3.18(2H, br-d), 3.72(2H, s), 4.20-4.28(1H, m),5.46(1H, br-t), 6.53(1H, d, J=2.8 Hz), 6.96-7.01(3H, m), 7.17-7.20(2H,m), 7.26-7.27(2H, m), 7.61(1H, d, J=8.0 Hz).ESI-Mass; 436(MH+).Example 297: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-propylcarbamoylmethyl)indole

A suspension of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(n-propylcarbamoyl)methyl]indoline(0.04 g) obtained in Example 150 and active manganese dioxide (0.08 g)in chloroform (30 ml) was vigorously stirred at 50° C. overnight. Thenthe reaction mixtures were filtered through celite and the residue waswashed with chloroform. After concentrating the filtrate under reducedpressure, the residue was recrystallized from chloroform/hexane to givethe title compound (0.03 g) as white needles (yield: 84.6%).

m.p.: 131.1-131.9° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 0.81(3H,t,J=7.4 Hz), 1.41(2H,tq,J=7.4,7.4Hz), 2.07-2.12(4H,m), 2.25-2.31(2H,m), 2.64-2.68(2H,m), 2.81-2.85(2H,m),3.71(2H,s), 4.20-4.28(1H,m), 5.43(1H,br-t), 6.53(1H,d,J=3.2 Hz),6.96-7.01(3H,m), 7.17-7.21(2H,m), 7.25-7.27(2H,m), 7.61(1H,d,J=8.0 Hz).ESI-Mass; 422(MH+).Example 298: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(tetramethylenecarbamoylmethyl)indoleoxalate

A suspension of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(tetramethylenecarbamoylmethyl)indoline(0.08 g) obtained in Example 155 and active manganese dioxide (0.07 g)in chloroform (30 ml) was vigorously stirred at 50° C. overnight. Thenthe reaction mixtures were filtered through celite and the residue waswashed with chloroform. After concentrating the filtrate under reducedpressure, the free compound (0.06 g) of the title compound was obtainedas a pale brown viscous compound (yield: 87.0%).

Next, this free compound was converted into an oxalate in a conventionalmanner, which was then reprecipitated from methanol/diethyl ether togive the title compound as a colorless powder.

Free compound:

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.78-1.93(4H,m), 2.09(4H,br-s),2.25-2.33(2H,m), 2.64-2.68(2H,m), 2.81-2.85(2H,m), 3.17(2H,br-d),3.45-3.51(4H,m), 3.78(2H,s), 4.24-4.32(1H,m), 6.49(1H,d,J=3.0 Hz),6.97-7.01(3H,m), 7.17-7.20(2H,m), 7.22(1H,d,J=3.0 Hz), 7.38(1H,s),7.55(1H,d,J=8.0 Hz).Oxalate:m.p.: 171.5-172.1° C.¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.72-1.79(2H,m), 1.83-1.90(2H,m),2.09-2.21(4H,m), 2.92-3.18(6H,m), 3.29(2H,t,J=7.0 Hz), 3.49(2H,t,J=7.0Hz), 3.49-3.56(2H,m), 3.70(2H,s), 4.58(1H,br-s), 6.45(1H,d,J=3.2 Hz),6.93(1H,dd,J=1.2,8.4 Hz), 7.16-7.20(2H,m), 7.33-7.37(2H,m),7.39-7.42(2H,m), 7.46(1H,d,J=8.4 Hz).ESI-Mass; 434(MH+).Example 299: Synthesis of1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindole

A suspension of1-[1-(2,4-difluorophenethyl)-piperidin-4-yl]-6-carbamoylmethylindoline(0.05 g) obtained in Example 225 and active manganese dioxide (0.10 g)in chloroform (30 ml) was vigorously stirred at 50° C. overnight. Thenthe reaction mixtures were filtered through celite and the residue waswashed with chloroform. After concentrating the filtrate under reducedpressure, the residue was recrystallized from chloroform/hexane to givethe title compound (0.02 g) as a white powder (yield: 41.7%).

m.p.: 156.9-157.8° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.03-2.12(4H,m), 2.25-2.31(2H,m),2.63-2.67(2H,m), 2.84-2.88(2H,m), 3.17(2H,br-d), 4.22-4.30(1H,m),5.54(2H,br-s), 6.52(1H,dd,J=0.8,3.2 Hz), 6.88(1H,dt,J=1.2,8.6 Hz),7.10(1H,ddd,J=0.8,7.0,8.0 Hz), 7.13-7.22(2H,m), 7.24(1H,d,J=3.6 Hz),7.38(1H,dd,J=0.4,8.4 Hz), 7.62-7.65(1H,m).ESI-Mass; 398(MH+).Example 300: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-hydroxyethyl)carbamoylmethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.20 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.104 g)and the resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, ethanolamine (320 ml) was added theretoand the mixture was further stirred overnight. After evaporating thesolvent under reduced pressure, water and ethyl acetate were added tothe residue. The organic layer was separated, washed successively withwater and brine and dried over magnesium sulfate. Then the solvent wasevaporated under reduced pressure to give a pale brown viscous oil (0.15g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.31 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, the manganese dioxide was filtered off and the solvent wasevaporated under reduced pressure. Then the residue was recrystallizedfrom chloroform/n-hexane to give the title compound (0.13 g) as a paleyellow powder.

m.p.: 140.0-141.2° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.08-2.21(4H,m), 2.28(2H,br-t),2.64-2.68(2H,m), 2.81-2.85(2H,m), 3.19(2H,br-d), 3.35-3.39(2H,m),3.67(2H,t,J=5.0 Hz), 3.74(2H,s), 4.19-4.28(1H,m), 5.90(1H,br-t),6.51(1H,br-d), 6.96-7.02(3H,m), 7.17-7.21(2H,m), 7.25(1H,d,J=3.2 Hz),7.31(1H,br-s), 7.61(1H,d,J=8.4 Hz).ESI-Mass; 424(MH+).Example 301: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-dimethylcarbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.19 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.10 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, a 2 M solution (2.50 ml) of dimethylaminein tetrahydrofuran was added thereto and the mixture was further stirredovernight. After evaporating the solvent under reduced pressure, waterand ethyl acetate were added to the residue. The organic layer wasseparated, washed successively with water and brine and dried overmagnesium sulfate. Then the solvent was evaporated under reducedpressure to give a pale brown viscous oil (0.13 g).

This substance was dissolved in chloroform (30 ml) and manganese dioxide(0.28 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, additional manganese dioxide (0.14 g) was added theretoand the mixture was stirred for 5 hr. Then the manganese dioxide wasfiltered off and the solvent was evaporated under reduced pressure togive a free compound (0.15 g) of the title compound as a pale brownviscous oil, which was then converted into an oxalate in a conventionalmanner.

m.p.: 170.1-170.6° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.14-2.24(4H,m), 2.83(3H,s),2.95-3.10(4H,m), 3.03(3H,s), 3.15(2H,br-s), 3.53(2H,br-d), 3.76(2H,s),4.58(1H,br-s), 6.45(1H,d,J=3.2 Hz), 6.91(1H,d,J=8.2 Hz),7.15-7.20(2H,m), 7.33-7.37(2H,m), 7.40(2H,br-s), 7.47(1H,d,J=8.2 Hz).ESI-Mass; 408(MH+).

Example 302: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-hydroxypiperidin-1-yl)carbonylmethyl)indole

1 -[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.21g) obtained in Example 146 was dissolved in N,N-dimethylformamide (5ml). To the resultant solution was added 1,1-carbonyldiimidazole (0.11g) and the resultant mixture was stirred in a nitrogen atmosphere atroom temperature for 15 min. Next, 4-hydroxypiperidine (0.56 g) wasadded thereto and the mixture was further stirred overnight. Afterevaporating the solvent under reduced pressure, water and ethyl acetatewere added to the residue. The organic layer was separated, washedsuccessively with water and brine and dried over magnesium sulfate. Thenthe solvent was evaporated under reduced pressure to give a pale brownviscous oil (0.18 g).

This residue (0.13 g) was dissolved in chloroform (30 ml) and manganesedioxide (0.33 g) was added thereto. After stirring the resultant mixtureat 50° C. for 10 hr, the manganese dioxide was filtered off and thesolvent was removed under reduced pressure. Then the residue wasrecrystallized from chloroform/n-hexane to give the title compound (0.16g) as colorless micaceous flakes.

m.p.: 190.5-192.2° C. (decomp.).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.22-1.50(2H,m), 1.62-1.69(1H,m),1.82-1.89(1H,m), 2.05-2.11(4H,m), 2.24-2.31(2H,m), 2.63-2.67(2H,m),2.80-2.84(2H,m), 3.15-3.24(4H,m), 3.76-3.88(2H,m), 3.88(2H,s),4.11-4.17(2H,m), 4.21-4.29(1H,m), 6.49(1H,d,J=3.6 Hz), 6.95-7.01(3H,m),7.17-7.20(2H,m), 7.22(1H,d,J=3.6 Hz), 7.30(1H,s), 7.56(1H,d,J=8.4 Hz).ESI-Mass: 464(MH+).Example 303: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[bis(2-hydroxyethyl)]carbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.20 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.10 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, diethanolamine (0.56 g) dissolved inN,N-dimethylformamide (1 ml) was added thereto and the mixture wasfurther stirred overnight. After evaporating the solvent under reducedpressure, water and ethyl acetate were added to the residue. The organiclayer was separated, washed successively with water and brine and driedover magnesium sulfate. Then the solvent was evaporated under reducedpressure to give a pale brown viscous oil (0.16 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.30 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, the manganese dioxide was filtered off and the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography (chloroform/methanol system) to give a freecompound (0.10 g) of the title compound as a pale brown viscous oil,which was then converted into an oxalate in a conventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.10(2H,br-d), 2.29(2H,br-q),3.98-3.08(4H,m), 3.16-3.21(2H,m), 3.39(2H,br-t), 3.45-3.58(8H,m),3.83(2H,s), 4.57-4.65(1H,m), 6.45(1H,d,J=3.2 Hz), 6.91(1H,d,J=8.0 Hz),7.17(2H,br-t), 7.33-7.37(2H,m), 7.40(2H,br-s), 7.47(1H,d,J=8.0 Hz).ESI-Mass; 468(MH+).Example 304: Synthesis of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,3-dihydroxypropan-2-yl)carbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.23 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.11 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, 2-amino-1,3-propanediol (Serinol, 0.27 g)was added thereto and the mixture was further stirred overnight. Afterevaporating the solvent under reduced pressure, water and ethyl acetatewere added to the residue. The organic layer was separated, washedsuccessively with water and brine and dried over magnesium sulfate. Thenthe solvent was evaporated under reduced pressure to give a pale brownviscous oil (0.20 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.27 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, additional manganese dioxide (0.19 g) was added theretofollowed by stirring for 6 hr. Then the manganese dioxide was filteredoff and the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (chloroform/methanolsystem) to give a free compound (0.09 g) of the title compound as a palebrown viscous oil, which was then converted into an oxalate in aconventional manner.

m.p.: 213.1-214.5° C. (decomp.).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.06-2.23(4H,m), 2.81-3.09(6H,m),3.41-3.47(6H,m), 3.52(2H,s), 3.67-3.75(1H,m), 4.49-4.57(1H,m),6.43(1H,d,J=3.2 Hz), 6.95(1H,d,J=8.4 Hz), 7.17(2H,br-t),7.32-7.36(2H,m), 7.41-7.46(3H,m), 7.72(1H,d,J=8.4 Hz).

ESI-Mass; 454(MH+).

Example 305: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethyl-indoline (0.22g) obtained in Example 146 was dissolved in N,N-dimethylformamide (5ml). To the resultant solution was added 1,1-carbonyldiimidazole (0.11g) and the resultant mixture was stirred under nitrogen atmosphere atroom temperature for 15 min. Next, a saturated solution (2 ml) ofammonia in methanol was added thereto and the mixture was furtherstirred overnight. After evaporating the solvent under reduced pressure,water and ethyl acetate were added to the residue. The organic layer wasseparated, washed successively with water and brine and dried overmagnesium sulfate. Then the solvent was evaporated under reducedpressure to give a pale brown viscous oil (0.11 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.24 g) was added thereto. After stirring the resultant mixture at 50°C. for 4 hr, additional manganese dioxide (0.12 g) was added theretofollowed by stirring overnight. Then the manganese dioxide was filteredoff and the solvent was evaporated under reduced pressure. The residuewas recrystallized from chloroform/n-hexane to give the title compound(0.08 g) as a pale yellow powder.

m.p.: 159.1-160.8° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.07-2.13(4H,m), 2.25-2.31(2H,m),2.64-2.68(2H,m), 2.81-2.85(2H,m), 3.18(2H,br-d), 3.73(2H,s),4.21-4.29(1H,m), 5.33(1H,br-s), 4.43(1H,br-s), 6.52(1H,dd,J=3.2 Hz),6.97-7.01(3H,m), 7.17-7.20(2H,m), 7.26(1H,d,J=3.2 Hz), 7.29(1H,s),7.62(1H,d,J=8.0 Hz).ESI-Mass; 380(MH+).Example 306: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(carbamoylmethyl)carbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethyl-indoline (0.22g) obtained in Example 146 was dissolved in N,N-dimethylformamide (5ml). To the resultant solution was added 1,1-carbonyldiimidazole (0.11g) and the resultant mixture was stirred under nitrogen atmosphere atroom temperature for 15 min. Next, a suspension of glycinamidehydrochloride (0.31 g) and triethylamine (395 ml) inN,N-dimethylformamide (10 ml) was added thereto and the mixture wasfurther stirred overnight. After evaporating the solvent under reducedpressure, water and ethyl acetate were added to the residue. The organiclayer was separated, washed successively with water and brine and driedover magnesium sulfate. Then the solvent was evaporated under reducedpressure to give a pale brown viscous oil (0.10 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.14 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, additional manganese dioxide (0.10 g) was added theretofollowed by stirring for 3.5 hr. Then the manganese dioxide was filteredoff and the solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (chloroform/methanolsystem) to give a free compound (0.06 g) of the title compound as a palebrown amorphous substance, which was then converted into an oxalate in aconventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.06-2.22(4H,m), 2.86-3.07(6H,m),3.57(2H,s), 3.65(2H,d,J=5.6 Hz), 4.56(1H,br-s), 7.44(1H,d,J=2.8 Hz),6.96(1H,d,J=7.8 Hz), 7.04(1H,br-s), 7.17(1H,br-t), 7.33-7.36(3H,m),7.41(1H,br-s), 7.46(1H,d,J=7.8 Hz), 7.50(1H,s), 8.13(1H,br-t).ESI-Mass; 437(MH+).Example 307: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-dimethylaminoethyl)carbamoylmethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.22 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.11 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, N,N-dimethylethylenediamine (310 ml) wasadded thereto and the mixture was further stirred overnight. Afterevaporating the solvent under reduced pressure, water and ethyl acetatewere added to the residue. The organic layer was separated, washedsuccessively with water and brine and dried over magnesium sulfate. Thenthe solvent was distilled off under reduced pressure to give a palebrown viscous oil (0.18 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.24 g) was added thereto. After stirring the resultant mixture at 50°C. for 9 hr, additional manganese dioxide (0.28 g) was added theretofollowed by stirring overnight. Then the manganese dioxide was filteredoff and the solvent was evaporated under reduced pressure. The residuewas recrystallized from chloroform/n-hexane to give the title compound(0.12 g) as a pale brown powder.

m.p.: 111.8-112.9° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.07-2.14(4H,m), 2.13(6H,s),2.24-2.32(2H,m), 2.32(2H,t,J=6.0 Hz), 2.64-2.68(2H,m), 2.81-2.85(2H,m),3.18(2H,br-d), 3.28(2H,dt,J=6.0,6.0 Hz), 3.69(2H,s), 4.21-4.29(1H,m),5.98(1H,br-t), 6.51(1H,d,J=3.4 Hz), 6.97-7.01(3H,m), 7.17-7.20(2H,m),7.24(1H,d,J=3.4 Hz), 7.30(1H,s), 7.59(1H,d,J=8.0 Hz).ESI-Mass; 451(MH+).Example 308: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanomethylcarbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.22 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.11 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, aminoacetonitrile hydrochloride (0.26 g)dissolved in N,N-dimethylformamide (10 ml) was added thereto. Afterfurther adding triethylamine (394 ml), the resultant mixture was stirredovernight. After evaporating the solvent under reduced pressure, waterand ethyl acetate were added to the residue. The organic layer wasseparated, washed successively with water and brine and dried overmagnesium sulfate. Then the solvent was evaporated under reducedpressure to give a pale brown viscous oil (0.17 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.25 g) was added thereto. After stirring the resultant mixture at 50°C. 8 hr, additional manganese dioxide (0.28 g) was added theretofollowed by stirring overnight. Then the manganese dioxide was filteredoff and the solvent was evaporated under reduced pressure. The residuewas purified successively by silica gel column chromatography(chloroform/methanol system) and NH silica gel column chromatography(chloroform/ethyl acetate system) to give a free compound (0.04 g) ofthe title compound as a pale brown viscous oil, which was then convertedinto an oxalate in a conventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.04-2.21(4H,m), 2.77-3.06(6H,m),3.41-3.46(2H,m), 3.58(2H,s), 4.13(2H,d,J=5.6 Hz), 4.53(1H,br-s),6.45(1H,d,J=3.2 Hz), 6.94(1H,d,J=8.6 Hz), 7.16(2H,br-t),7.32-7.36(2H,m), 7.44(2H,br-s), 7.48(1H,d,J=8.6 Hz), 8.69(1H,br-t).

ESI-Mass; 419(MH+).

Example 309: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-methoxyethyl)carbamoylmethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.22 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.11 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, 2-methoxyethylamine (245 ml) was addedthereto and the mixture was further stirred for 4 hr. After evaporateingthe solvent under reduced pressure, water and ethyl acetate were addedto the residue. The organic layer was separated, washed successivelywith water and brine and dried over magnesium sulfate. Then the solventwas evaporated under reduced pressure to give a pale brown viscous oil(0.19 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.31 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, additional manganese dioxide (0.27 g) was added theretofollowed by stirring for 5 hr. Then manganese dioxide (0.19 g) wasfurther added thereto and the resultant mixture was stirred foradditional 1 hr. Then the manganese dioxide was filtered off and thesolvent was evaporated under reduced pressure. The residue wasrecrystallized from chloroform/n-hexane to give the title compound (0.13g) as a colorless powder.

m.p.: 113.2-114.4° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.07-2.13(4H,m), 2.25-2.31(2H,m),2.64-2.68(2H,m), 2.81-2.85(2H,m), 3.18(2H,br-d), 3.26(3H,s),3.39(4H,br-d), 3.71(2H,s), 4.21-4.29(1H,m), 5.81(1H,br-s),6.52(1H,d,J=3.4 Hz), 6.96-7.01(3H,m), 7.17-7.21(2H,m), 7.26(1H,d,J=3.4Hz), 7.28(1H,s), 7.60(1H,d,J=8.0 Hz).ESI-Mass; 438(MH+).Example 310: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-fluoroethyl)carbamoylmethylindole1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.22 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.11 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, 2-fluoroethylamine hydrochloride (0.30 g)dissolved in N,N-dimethylformamide (5 ml) was added thereto.Afterfurther addingtriethylamine (397 ml), the mixture was stirred for 4hr. After evaporating the solvent under reduced pressure, water andethyl acetate were added to the residue. The organic layer wasseparated, washed successively with water and brine and dried overmagnesium sulfate. Then the solvent was evaporated under reducedpressure to give pale brown crystals (0.19 g).

These crystals were dissolved in chloroform (30 ml) and manganesedioxide (0.30 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, additional manganese dioxide (0.26 g) was addedthereto followed by stirring for 5 hr. Then manganese oxide (0.19 g) wasfurthermore added and the resultant mixture was stirred for additional 2hr. Next, the manganese dioxide was filtered off and the solvent wasevaporated under reduced pressure. The residue was recrystallized fromchloroform/n-hexane to give the title compound (0.15 g) as a colorlesspowder.

m.p.: 163.3-163.8° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.05-2.13(4H,m), 2.25-2.31(2H,m),2.64-2.68(2H,m), 2.81-2.85(2H,m), 3.18(2H,br-d),3.50(2H,ddt,J=4.8,28.0,4.8 Hz), 3.74(2H,s), 4.21-4.29(1H,m),4.43(2H,dt,J=47.2,4,8 Hz), 5.80(1H,br-t), 6.53(1H,d,J=3.2 Hz),6.97-7.01(3H,m), 7.17-7.20(2H,m), 7.26-7.28(2H,m), 7.62(1H,d,J=8.0 Hz).ESI-Mass; 426(MH+).Example 311: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(ethylcarbamoyl)ethyl]indoleoxalate311-1)1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[2-(ethoxycarbonyl)vinyl]indole

55% oily sodium hydride (0.46 g) was washed with n-hexane and suspendedin tetrahydrofuran (1 ml) followed by stirring under ice-cooling. Thenethyl diethylphosphonoacetate (2.37 g) dissolved in tetrahydrofuran (7ml) was added thereto and the resultant mixture was stirred at roomtemperature for 30 min. Next,1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindole (3.53 g) obtainedin Example 130 dissolved in tetrahydrofuran (10 ml) was added theretoand the resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 2 days. After evaporating the solvent under reducedpressure, water and ethyl acetate were added to the residue. The organiclayer was separated, washed successively with water and brine and driedover magnesium sulfate. Then the solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane system) to give the titlecompound (3.59 g) as yellow crystals.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.36(3H,t,J=7.2 Hz), 2.08-2.14(4H,m),2.26-2.33(2H,m), 2.65-2.69(2H,m), 2.81-2.85(2H,m), 3.20(2H,br-d),4.28(2H,q,J=7.2 Hz), 4.23-4.32(1H,m), 6.47(1H,d,J=16.0 Hz),6.53(1H,d,J=3.2 Hz), 6.97-7.02(2H,m), 7.17-7.21(2H,m), 7.32(1H,d,J=3.2Hz), 7.34(1H,d,J=8.4 Hz), 7.52(1H,s), 7.61(1H,d,J=8.4 Hz),7.84(1H,d,J=16.0 Hz).311-2)1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[2-(ethoxy-carbonyl)ethyl]indole

The above1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(ethoxycarbonyl)vinyl]indole(1.89 g) was dissolved in a mixture of ethanol (40 ml) and ethyl acetate(20 ml). Then 10% Pd/C (0.10 g) was added thereto and catalyticreduction was carried out under atmospheric pressure overnight. Afterfiltering off the catalyst, the solvent was evaporated under reducedpressure to give the title compound (1.87 g) as a colorless viscous oil.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.25(3H,t,J=7.2 Hz), 2.06-2.12(4H,m),2.24-2.31(2H,m), 2.64-2.70(4H,m), 2.81-2.85(2H,m), 3.08(2H,t,J=8.0 Hz),3.18(2H,br-d), 4.14(2H,q,J=7.2 Hz), 4.19-4.27(1H,m), 6.48(1H,d,J=3.2Hz), 6.95-7.01(3H,m), 7.17-7.20(4H,m), 7.54(1H,d,J=8.0 Hz).311-3) 1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(2-carboxyethyl)indole

The above1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(ethoxycarbonyl)ethyl]indole(1.85 g) was dissolved in methanol (25 ml). Then a 5 N aqueous solution(1.75 ml) of sodium hydroxide was added thereto and the resultantmixture was stirred at room temperature overnight. After removing thesolvent under reduced pressure, the residue was neutralized with 5 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed successively with water and brine and dried over magnesiumsulfate. After evaporating the solvent under reduced pressure, the titlecompound (1.70 g) was obtained as a pale brown amorphous substance.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.79-1.82(2H,m), 2.32-2.43(4H,m),2.78-2.84(4H,m), 2.92-2.97(2H,m), 3.13(2H,t,J=7.4 Hz), 3.20(2H,br-d),4.14-4.22(1H,m), 6.40(1H,d,J=3.2 Hz), 6.96-7.03(3H,m), 7.05(1H,d,J=3.2Hz), 7.16-7.20(2H,m), 7.33(1H,s), 7.49(1H,d,J=8.0 Hz).311-4)1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(2-ethylcarbamoyl)ethyl]indoleoxalate

The above1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-carboxyethyl)indole (0.10g) was dissolved in N,N-dimethylformamide (2 ml). To the resultantsolution was added 1,1-carbonyldiimidazole (0.05 g) and the resultantmixture was stirred under nitrogen atmosphere at room temperature for 15min. Next, a 70% aqueous solution (106 ml) of ethylamine was addedthereto and the mixture was stirred overnight. After evaporating thesolvent under reduced pressure, water and ethyl acetate were added tothe residue. The organic layer was separated, washed successively withwater and brine and dried over magnesium sulfate. Then the solvent wasevaporated under reduced pressure and the residue was purified byNH-silica gel column chromatography (ethyl acetate/n-hexane system) togive a free compound (0.05 g) of the title compound as a colorlessviscous oil, which was then converted into an oxalate in a conventionalmanner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.05(2H,br-d), 2.13-2.22(2H,m),2.39(2H,t,J=7.8 Hz), 2.81(2H,br-t), 2.89-2.95(4H,m), 3.01-3.09(4H,m),3.42(2H,br-d), 4.48-4.56(1H,m), 6.41(1H,d,J=3.2 Hz), 6.89(1H,d,J=8.0Hz), 7.16(2H,br-t), 7.32-7.37(3H,m), 7.39(1H,d,J=3.2 Hz),7.43(1H,d,J=8.0 Hz), 7.82(1H,t,J=5.4 Hz).ESI-Mass; 422(MH+).Example 312: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(pyrrolidin-1-yl)ethyl]carbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.21 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.11 g) andthe resultantmixturewas stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, 1-(2-aminoethyl)pyrrolidine (353 ml) wasadded thereto and the mixture was stirred for additional4.5 hr. Afterevaporating the solvent under reduced pressure, water and ethyl acetatewere added to the residue. The organic layer was separated, washedsuccessively with water and brine and dried over magnesium sulfate. Thenthe solvent was evaporated under reduced pressure to give a pale brownviscous oil (0.19 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.17 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, additional manganese dioxide (0.17 g) was added theretofollowed by stirring for 7 hr. Then manganese oxide (0.17 g) wasfurthermore added and the resultant mixture was stirred for additional 5hr. Next, the manganese dioxide was filtered off and the solvent wasremoved under reduced pressure to give a free compound (0.19 g) of thetitle compound as a pale brown viscous oil, which was then convertedinto an oxalate in a conventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.78-1.82(4H,m), 1.95(2H,br-d),2.06-2.16(2H,m), 2.41(2H,br-t), 2.70-2.74(2H,m), 2.81-2.85(2H,m),2.93-2.98(6H,m), 3.20(2H,br-d), 3.28-3.34(2H,m), 3.50(2H,s),4.32-4.40(1H,m), 6.40(1H,d,J=3.2 Hz), 6.94(1H,d,J=9.2 Hz),7.12(2H,br-t), 7.28-7.32(2H,m), 7.42-7.45(3H,m), 8.30(1H,br-t).ESI-Mass; 477(MH+).Example 313: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(morpholin-4-yl)ethyl]carbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.22 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.11 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, 4-(2-aminoethyl)morpholine (379 ml) wasadded thereto and the mixture was stirred for additional 4 hr. Afterevaporating the solvent under reduced pressure, water and ethyl acetatewere added to the residue. The organic layer was separated, washedsuccessively with water and brine and dried over magnesium sulfate. Thenthe solvent was evaporated under reduced pressure to give a pale brownviscous oil (0.19 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.17 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, additional manganese dioxide (0.17 g) was added theretofollowed by stirring for 8 hr. Then manganese oxide (0.17 g) wasfurthermore added and the resultant mixture was stirred for additional 3hr. Then manganese dioxide (0.08) g was further added and the mixturewas stirred for 1.5 hr. Then manganese dioxide (0.08) g was furthermoreadded and the mixture was stirred for additional 5 hr. Next, themanganese dioxide was filtered off and the solvent was distilled offunder reduced pressure to give a free compound (0.20 g) of the titlecompound as a pale brown viscous oil, which was then converted into anoxalate in a conventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.04(2H,br-d), 2.17-2.27(4H,m),2.40-2.44(6H,m), 2.79(2H,br-t), 2.91-2.95(2H,m), 2.98-3.03(2H,m),3.19(2H,br-q), 3.42(2H,br-d), 3.50(2H,s), 3.53(4H,br-t),4.47-4.55(1H,m), 6.43(1H,d,J=3.2 Hz), 6.96(1H,dd,J=0.8,8.0 Hz),7.13-7.18(2H,m), 7.32-7.35(2H,m), 7.42(1H,d,J=3.2 Hz), 7.45-7.47(2H,m),7.93(1H,t,J=5.6 Hz).ESI-Mass; 493(MH+).Example 314: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(pyridin-4-yl)methylcarbamoylmethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.21 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.11 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, 4-aminomethylpyridine (283 ml) was addedthereto and the mixture was stirred for additional 6 hr. Afterevaporating the solvent under reduced pressure, water and ethyl acetatewere added to the residue. The organic layer was separated, washedsuccessively with water and brine and dried over magnesium sulfate. Thenthe solvent was evaporated under reduced pressure to give a pale brownviscous oil (0.20 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.37 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, additional manganese dioxide (0.18 g) was added theretofollowed by stirring for 3 hr. Next, the manganese dioxide was filteredoff and the solvent was evaporated under reduced pressure to give thetitle compound (0.16 g) as a pale yellow amorphous solid.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.07-2.16(4H,m), 2.24-2.31(2H,m),2.64-2.68(2H,m), 2.81-2.85(2H,m), 3.18(2H,br-d), 3.81(2H,s),4.19-4.27(1H,m), 4.39(2H,d,J=6.0 Hz), 5.89(1H,t,J=6.0 Hz),6.53(1H,d,J=3.2 Hz), 6.97-7.01(3H,m), 7.06(2H,d,J=5.8 Hz),7.17-7.20(2H,m), 7.27(1H,d,J=3.2 Hz), 7.29(1H,s), 7.63(1H,d,J=8.0 Hz),8.48(2H,d,J=5.8 Hz).ESI-Mass; 471(MH+).Example 315: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(pyridin-2-yl)ethyl]carbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethyl-indoline (0.23g) obtained in Example 146 was dissolved in N,N-dimethylformamide (5ml). To the resultant solution was added 1,1-carbonyldiimidazole (0.11g) and the resultant mixture was stirred under nitrogen atmosphere atroom temperature for 15 min. Next, 2-(2-aminoethyl)pyridine (352 ml) wasadded thereto and the mixture was stirred for additional 6 hr. Afterevaporating the solvent under reduced pressure, water and ethyl acetatewere added to the residue. The organic layer was separated, washedsuccessively with water and brine and dried over magnesium sulfate. Thenthe solvent was evaporated under reduced pressure to give a pale brownviscous oil (0.23 g).

This residue was dissolved in chloroform (30 ml) and manganese dioxide(0.42 g) was added thereto. After stirring the resultant mixture at 50°C. overnight, additional manganese dioxide (0.21 g) was added theretofollowed by stirring for 7.5 hr. Next, the manganese dioxide wasfiltered off and the solvent was evaporated under reduced pressure togive a free compound (0.23 g) of the title compound as a pale brownviscous oil, which was then converted into an oxalate in a conventionalmanner.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.08(2H,br-d), 2.23-2.34(2H,m),2.06(2H,t,J=7.2 Hz), 2.93-3.00(4H,m), 3.11-3.15(2H,m), 3.41(2H,br-q),3.48(2H,s), 3.52(2H,br-d), 4.54-4.62(1H,m), 6.44(1H,d,J=3.0 Hz),6.91(1H,d,J=9.2 Hz), 7.15-7.20(4H,m), 7.33-7.36(2H,m), 7.42(1H,d,J=3.0Hz), 7.44-7.46(2H,m), 7.61(1H,dt,J=2.0,8.6 Hz), 8.07(1H,t,J=5.6 Hz),8.44(1H,br-d).ESI-Mass; 485(MH+).Example 316: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.29 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.15 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, a 40% aqueous solution (662 ml) ofmethylamine was added thereto and the mixture was stirred overnight.After evaporating the solvent under reduced pressure, water and ethylacetate were added to the residue. The organic layer was separated,washed successively with water and brine and dried over magnesiumsulfate. Then the solvent was evaporated under reduced pressure to givepale brown crystals (0.22 g).

These crystals were dissolved in chloroform (30 ml) and manganesedioxide (0.49 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, additional manganese dioxide (0.24 g) was addedthereto followed by stirring for 2 hr. Then manganese dioxide (0.19 g)was further added and the resultant mixture was stirred for 2 hr. Next,the manganese dioxide was filtered off and the solvent was evaporatedunder reduced pressure. The residue was recrystallized fromchloroform/n-hexane to give the title compound (0.18 g) as a pale brownpowder.

m.p.: 149.4-150.5° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.05-2.13(4H,m), 2.25-2.31(2H,m),2.64-2.68(2H,m), 2.73(3H,d,J=4.8 Hz), 2.81-2.85(2H,m), 3.18(2H,br-d),3.72(2H,s), 4.20-4.28(1H,m), 5.40(1H,br-s), 6.53(1H,d,J=3.2 Hz),6.95-7.01(3H,m), 7.17-7.20(2H,m), 7.26-7.27(2H,m), 7.61(1H,d,J=7.6 Hz).ESI-Mass; 394(MH+).

Example 317: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-methoxypyridin-5-yl)carbonylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[(2-methoxypyridin-5-yl)hydroxymethyl]indoline(0.16 g) obtained in Example 189 was dissolved in chloroform (30 ml). Tothe resultant solution was added manganese dioxide (0.30 g) and theresultant mixture was stirred at 50° C. overnight. Next, the manganesedioxide was filtered off and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/n-hexane system) to give a free compound (0.07 g) of thetitle compound as a pale brown viscous oil, which was then convertedinto an oxalate in a conventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.04-2.11(2H,m), 2.16-2.25(2H,m),2.75(2H,br-t), 2.89-2.97(4H,m), 3.98(3H,s), 4.68-4.76(1H,m),6.65(1H,d,J=3.2 Hz), 7.00(1H,d,J=8.8 Hz), 7.15(2H,br-t),7.31-7.34(2H,m), 7.44(1H,d,J=8.4 Hz), 7.70(1H,d,J=8.4 Hz),7.80(1H,d,J=3.2 Hz), 8.07(1H,s), 8.11(1H,dd,J=2.4,8.8 Hz),8.60(1H,d,J=2.4 Hz).ESI-Mass; 458(MH+).Example 318: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(2-methoxypyridin-5-yl)hydroxymethyl]indoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(2-methoxypyridin-5-ylcarbonyl)indole(0.07 g) obtained in Example 317 was dissolved in methanol (10 ml). Tothe resultant solution was added sodium borohydride in portions. Afterconfirming the disappearance of the starting compound by thin layerchromatography, the solvent was evaporated under reduced pressure. Thenwater was added to the residue followed by extraction with ethylacetate. The organic layer was washed successively with water and brineand dried over magnesium sulfate. Then the solvent was evaporated underreduced pressure to give a free compound (0.11 g) of the title compoundas a colorless viscous oil, which was then converted into an oxalate ina conventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.03-2.08(2H,m), 2.13-2.21(2H,m),2.75-3.00(6H,m), 3.40(2H,br-d), 3.80(2H,s), 4.52-4.60(1H,m),6.42(1H,d,J=3.2 Hz), 6.72(1H,d,J=8.6 Hz), 6.96(1H,d,J=8.6 Hz),7.16(2H,br-t), 7.32-7.35(2H,m), 7.44-7.46(2H,m), 7.62(1H,dd,J=2.2,8.6Hz), 7.65(1H,s), 8.19(1H,d,J=2.2 Hz).ESI-Mass; 460(MH+).Example 319: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyproyl)indole oxalate

1-[1-[(4-Fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.10 g)obtained in Example 130 was dissolved in tetrahydrofuran (5 ml) andstirred under ice cooling. To the resultant solution was added a 1.0 Msolution (0.5 ml) of ethylmagnesium bromide in tetrahydrofuran and theresultant mixture was stirred for 25 min. Next, a 1.0 M solution (0.5ml) of ethyl magnesium bromide in tetrahydrofuran was further addedthereto and the resultant mixture was stirred for additional 15 min. Tothe reaction mixtures were successively added a saturated aqueoussolution of ammonium chloride, water and ethyl acetate. The organiclayer was separated, washed successively with water and brine and driedover magnesium sulfate. Then the solvent was evaporated under reducedpressure to give a free compound (0.10 g) of the title compound as apale brown viscous oil, which was then converted into an oxalate in aconventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 0.85(3H,t,J=7.4 Hz), 1.62-1.75(2H,m),2.08(2H,br-d), 2.19-2.29(2H,m), 2.93-2.99(4H,m), 3.08-3.12(2H,m),3.49(2H,br-d), 4.54(1H,t,J=6.4 Hz), 4.59-4.65(1H,m), 6.43(1H,d,J=3.0Hz), 7.00(1H,d,J=8.0 Hz), 7.17(2H,br-t), 7.33-7.36(2H,m),7.41(1H,d,J=3.0 Hz), 7.47(1H,d,J=8.0 Hz), 7.49(1H,s).ESI-Mass; 381(MH+).Example 320: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-1-methylethyl)indoline

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-1-methylethyl)indoline(0.1 g) obtained in Example 139 and activated manganese dioxide (0.5 g)were treated as in Example 288 to give the title compound (0.07 g) as apale yellow oil (yield: 70.3%).

Next, this product was converted into an oxalate in a conventionalmanner.

Oxalate:

m.p.: 97-99° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.49(6H,s), 2.04-2.15(2H,m),2.16-2.30(2H,m), 2.92-3.06(4H,m), 3.08-3.19(2H,m), 3.47-3.56(2H,m),4.58-4.68(1H,m), 6.42(1H,d,J=3.2 Hz), 7.13(1H,dd,J=8.4,1.2 Hz),7.13-7.21(2H,m), 7.32-7.37(2H,m), 7.40(1H,d,J=3.2 Hz), 7.50(1H,d,J=8.4Hz), 7.63(2H,br-s).FAB-Mass; 381(MH+).Example 121: Synthesis of1-[1-(4-fluorophenethyl)piperdin-4-yl]-6-(3-hydydroxypropyl)indoline

A solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindole(0.20 g) obtained in Example 130 in tetrahydrofuran (2 ml) was addeddropwise at room temperature into a solution prepared by adding triethylphosphonoacetate (0.14 g) to a suspension of sodium hydride (0.03 g) intetrahydrofuran (5 ml). After 1 hr, a saturated aqueous solution (10 ml)of ammonium chloride was added thereto and the mixture was extractedwith ethyl acetate. The extract was washed successively with water andbrine, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue was dissolved in ethanol (10 ml) and thenhydrogenated in the presence of 10% palladium carbon (0.05 g) atordinary temperature under atmospheric pressure. After 2 hr, thereaction mixturew were filtered and the filtrate was concentrated. Theresidue was dissolved in tetrahydrofuran (3 ml) and the resultingsolution was added dropwise into a suspension of lithium aluminumhydride (0.03 g) in tetrahydrofuran (5 ml). After stirring the reactionmixtures at room temperature for 1 hr, water (0.03 ml), 5 N sodiumhydroxide (0.09 ml) and further water (0.03 ml) were added thereto inthis order. The resulting precipitate was filtered off. After washingwith ethyl acetate, the filtrate was concentrated. The residue waspurified by silica gel column chromatography (dichloromethane/methanolsystem) to give the title compound (0.05 g) as a pale yellow powder(yield: 23%)

m.p.: 131-133° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.90-2.05(4H,m), 2.20-2.29(2H,m),2.55-2.62(2H,m), 2.74-2.81(2H,m), 2.81(3H,s), 3.06-3.13(2H,m),4.25(2H,d,J=6.4 Hz), 4.26-4.38(1H,m), 6.42(1H,d,J=3.2 Hz), 7.02(1H,dd,J=8.0,1.2 Hz), 7.08-7.14(2H,m), 7.27-7.33(2H,m), 7.47-7.53(3H,m).ESI-Mass; 381(MH+).Example 322: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonamidomethylindole322-1) 1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-formylindole

A suspension of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline(3.60 g) obtained in Example 130 and activated manganese dioxide (15.0g) in chloroform (100 ml) was heated under reflux for 6 hr undervigorous stirring. Then the reaction mixtures were filtered throughcelite and the residue was washed with chloroform. After concentratingthe filtrate under reduced pressure, the residue was recrystallized fromethyl acetate/hexane to give the title compound (2.45 g) as a yellowpowder (yield: 68.4%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.09-2.42(6H,m), 2.67-2.75(2H,m),2.83-2.91(2H,m), 3.19-3.28(2H,br-d), 4.35-4.45(1H,m), 6.61(1H,d,J=3.2Hz), 6.95-7.05(2H,m), 7.16-7.23(2H,m), 7.48(1H,d,J=3.2 Hz),7.62(1H,dd,J=8.0,1.2 Hz), 7.72(1H,d,J=8.0 Hz), 7.98(1H,s), 10.07(1H,s).322-2)1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-formylindole (3.78 g),hydroxylamine hydrochloride(0.90 g) and anhydrous sodium acetate (1.06g) were stirred in ethanol (60 ml) at room temperature for 2 hr. Thenthe liquid reaction mixture was concentrated and the residue waspartitioned between ethyl acetate (150 ml) and a 1 N aqueous solution(30 ml) of sodium hydroxide. The ethyl acetate layer was washedsuccessively with water and brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was crystallized fromether/hexane and the crystals were collected by filtration, washed withhexane and dried to give the title compound (3.60 g) as a pale yellowpowder (yield: 91.3%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.03-37(6H,m), 2.61-2.74(2H,m),2.81-2.91(2H,m), 3.15-3.27(2H,m), 4.20-4.32(1H,m), 6.51(0.5H,d,J=3.2Hz), 6.68(0.5H,d,J=3.2 Hz), 6.95-7.02(2H,m), 7.14-7.22(2H,m),7.31(0.5H,d,J=3.2 Hz), 7.32(0.5H,dd,J=8.0,1.2 Hz),7.38(0.5H,dd,J=8.0,1.2 Hz), 7.45(0.5H,d,J=3.2 Hz), 7.58-7.63(1H,m),7.66(0.5H,d,J=8.0 Hz), 7.74(0.5H,br-s), 8.32(0.5H,s).322-3) 1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole

Into a suspension of aluminum lithium hydride (1.0 g) in tetrahydrofuran(100 ml) was added dropwise at room temperature a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindole (3.60g) in tetrahydrofuran (50 ml) under ice cooling and stirring, and theresultant mixture was heated under reflux for 3 hr. Under cooling withice water, water (1 ml), a 5 N aqueous solution (3 ml) of sodiumhydroxide and further water (1 ml) were carefully added dropwise intothe reaction mixtures in this order followed by vigorous stirring. Theresulting precipitate was filtered off and the filtrate was concentratedunder reduced pressure. Then the residue was purified by NH silica gelcolumn chromatography (ethyl acetate) to give the title compound (2.56g) as a pale yellow powder (yield: 73.9%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.86-2.18(4H,m), 2.22-2.32(2H,m),2.61-2.70(2H,m), 2.78-2.87(2H,m), 3.10-3.18(2H,m), 4.05(2H,d,J=4.2 Hz),4.20-4.28(1H,m), 6.46(1H,d,J=3.2 Hz), 6.95-7.03(2H,m),7.05(1H,dd,J=8.4,1.6 Hz), 7.14-7.19(2H,m), 7.21(1H,d,J=3.2 Hz),7.50-7.53(1H,m), 7.53(1H,d,J=8.4 Hz).322-4)1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-methanesulfonamidomethylindole

Into a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.12 g)obtained in the above Example and triethylamine (0.5 g) in ethyl acetate(15 ml) was added dropwise under ice cooling methanesulfonyl chloride(0.08 ml) and the resultant mixture was stirred at room temperature for1 hr. After adding a 1 N aqueous solution (2 ml) of sodium hydroxide andwater (15 ml), the reaction mixtures were extracted with ethyl acetate.The ethyl acetate layer was washed successively with water and brine,dried over magnesium sulfate and concentrated under reduced pressure.The residue was crystallized from ether/hexane and the crystals werecollected by filtration, washed with hexane and dried to give the titlecompound (0.11 g) as a white powder (yield: 75%).

m.p.: 121-122° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.90-2.05(4H,m), 2.20-2.29(2H,m),2.55-2.62(2H,m), 2.74-2.81(2H,m), 2.81(3H,s), 3.06-3.13(2H,m),4.25(2H,d,J=6.4 Hz), 4.26-4.38(1H,m), 6.42(1H,d,J=3.2 Hz),7.02(1H,dd,J=8.0,1.2 Hz), 7.08-7.14(2H,m), 7.27-7.33(2H,m),7.47-7.53(3H,m).ESI-Mass; 430(MH+).Example 323: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isopropylsulfonamidomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.20 g),triethylamine (0.3 ml) and isopropylsulfonyl chloride (0.1 ml) weretreated as in Example 322-4) to give the title compound (0.06 g) as awhite powder (yield: 23%).

m.p.: 90-92° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.38(6H,d,J=7.2 Hz), 2.05-2.18(4H,m),2.22-2.36(2H,m), 2.60-2.75(2H,m), 2.79-2.90(2H,m), 3.05-3.25(3H,m),4.20-4.35(1H,m), 4.35-4.50(3H,m), 6.52(1H,d,J=3.2 Hz), 6.99(2H,t,J=8.8Hz), 7.05(1H,d,J=8.0 Hz), 7.19(2H,dd,J=5.4,8.8 Hz), 7.27(1H,d,J=3.2 Hz),7.38(1H,s), 7.60(1H,d,J=8.0 Hz).MS m/e; 458(MH+).Example 324: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-n-propylsulfonamidomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.25 g),triethylamine (0.4 ml) and n-propylsulfonyl chloride (0.3 ml) weretreated as in Example 322-4) to give the title compound (0.17 g) as abeige powder (yield: 53%).

m.p.: 80-81° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 0.99(3H,t,J=7.4 Hz), 1.76-1.88(2H,m),2.02-2.20(4H,m), 2.34-2.37(2H,m), 2.60-2.74(2H,m), 2.76-3.00(4H,m),3.12-3.28(2H,m), 4.20-4.34(1H,m), 4.43(2H,d,J=5.6 Hz), 4.48(1H,br-s),6.52(1H,d,J=3.2 Hz), 6.99(2H,t,J=8.4 Hz), 7.05(1H,d,J=8.0 Hz),7.19(2H,dd,J=5.8,8.4 Hz), 7.28(1H,d,J=3.2 Hz), 7.38(1H,s),7.61(1H,d,J=8.0 Hz).MS m/e; 458(MH+).Example 325: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-chloropropyl)sulfonamidomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.25 g),triethylamine (0.4 ml) and 3-chloropropylsulfonyl chloride (0.1 ml) weretreated as in Example 322-4) to give the title compound (0.25 g) as awhite powder (yield: 71%).

m.p.: 143-145° C.

¹H-NMR(400 MHz,CDCl₆); δ(ppm) 2.06-2.16(4H,m), 2.19-2.36(4H,m),2.63-2.72(2H,m), 2.79-2.88(2H,m), 3.09(2H,t,J=7.4 Hz), 3.15-3.24(2H,m),3.59(2H,t,J=6.4 Hz), 4.20-4.34(1H,m), 4.44(2H,d,J=5.6 Hz),4.56(1H,br-s), 6.52(1H,d,J=3.2 Hz), 6.99(2H,t,J=8.4 Hz), 7.05(1H,d,J=8.4Hz), 7.19(2H,dd,J=5.6,8.4 Hz), 7.28(1H,d,J=3.2 Hz), 7.38(1H,s),7.62(1H,d,J=8.4 Hz).MS m/e; 492, 494(MH+).Example 326: Synthesis of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,3-propanesultam-2-yl)methylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(3-chloropropyl)sulfonamidomethylindole(144 mg) obtained in the above Example325 wasdissolvedinN,N-dimethylformamide (4 ml). Then sodium hydride (40 mg, 60-70% oily)was added thereto at room temperature and the resultant mixture wasstirred for 20 min. After adding water, the mixture was extracted withethyl acetate and dried over magnesium sulfate. After evaporating thesolvent, the residue was purified by silica gel column chromatography(ethyl acetate) to give the title compound (110 mg) as a colorlessamorphous substance (yield: 83%).

This amorphous substance was dissolved in ethanol (5 ml) and oxalic acid(20 mg) dissolved in ethanol (1 ml) was added thereto. The resultingsalt was powdered by adding ethyl acetate and collected by filtration togive an oxalate (82 mg) of the title compound as a white powder.

Oxalate:

m.p.: 171-172° C.

Free compound:

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.10-2.38(4H,m), 2.22-2.36(4H,m),2.62-2.72(2H,m), 2.78-2.88(2H,m), 3.06-3.28(6H,m), 4.20-4.38(1H,m),4.30(2H,s), 6.52(1H,d,J=3.2 Hz), 6.99(2H,t,J=8.4 Hz), 7.07(1H,d,J=8.0Hz), 7.19(2H,dd,J=5.6 and 8.4 Hz), 7.27(1H,d,J=3.2 Hz), 7.37(1H,s),7.59(1H,d,J=8.0 Hz).MS m/e; 456(MH+).Example 327: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-propionylaminomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-propionylaminomethylindoline(0.16 g) obtained in Example 156 and activated manganese dioxide (0.8 g)were treated as in Example 288 to give the title compound (0.12 g) as awhite powder

(yield: 75.3 ).

m.p.: 141-142° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.18(3H,t,J=7.2 Hz), 2.06-2.15(2H,m),2.51(2H,q,J=7.2 Hz), 2.28-2.50(2H,m), 2.64-2.98(4H,m), 3.16-3.35(2H,m),4.22-4.34(1H,m), 4.56(2H,d,J=6 Hz), 6.51(1H,d,J=3.2 Hz),6.96-7.05(2H,m), 7.16-7.23(2H,m), 7.24(1H,d,J=3.2 Hz), 7.36(1H,br-s),7.58(1H,d,J=8.0 Hz).ESI-Mass; 408(MH+).Example 328: Synthesis of3-chloro-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole (0.1 g)obtained in Example was reacted with 1-chlorosuccinimide (0.04 g) inbenzene (10 ml) at 80° C. for 1 hr. Then the liquid reaction mixture wasdiluted with ethyl acetate (20 ml), washed successively with water andbrine, dried over magnesium sulfate and concentrated under reducedpressure. The residue was crystallized from ether/hexane and thecrystals were collected by filtration, washed with hexane and dried togive the title compound (0.04 g) as a white powder (yield: 36.8%).

m.p.: 101-102° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.95-2.15(4H,m), 2.03(3H,s),2.20-2.50(2H,m), 2.72-3.00(4H,m), 3.28-3.40(2H,m), 4.20-4.30(1H,m),4.54(2H,d,J=6.4 Hz), 6.95-7.04(2H,m), 7.10(1H,d,J=8.0 Hz),7.17-7.24(3H,m), 7.35(1H,s), 7.55(1H,d,J=8.0 Hz).

ESI-Mass; 428(MH+).

Example 329: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-hydroxybutyroylamidomethyl)indoleoxalate

4-Acetoxybutyric acid (0.07 g) synthesized in accordance with the methoddescribed in Tetrahedron., 45(24), 7783-7794, 1989. was reacted with1,1′-carbonyldiimidazole (0.08 g) in chloroform (5 ml). Next,1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (0.13 g)obtained in Example 322-3) was added thereto and the resultant mixturewas stirred at room temperature for 3 hr. After concentrating thereaction mixtures, a 5 N aqueous solution of sodium hydroxide (2 ml) andmethanol (10 ml) were added to the residue. After reacting at 50° C. for1 hr, the solvent was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography(dichloromethane/methanol system). The resulting pale yellow oil wasconverted into an oxalate in a conventional manner to give the oxalate(0.04 g) of the title compound as a pale brown amorphous substance(yield: 20.5%).

Oxalate:

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.68(2H,m), 2.08-2.34(4H,m),2.18(2H,t,J=7.6 Hz), 2.96-3.29(6H,m), 3.39(2H,t,J=6.8 Hz),3.56-3.66(2H,m), 4.36(2H,d,J=5.2 Hz), 4.58-4.70(1H,m), 6.46(1H,d,J=3.6Hz), 6.96(1H,d,J=8.0 Hz), 7.15-7.23(2H,m), 7.32-7.46(3H,m),7.50(1H,d,J=8.0 Hz), 8.26-8.33(1H,m).ESI-Mass; 438(MH+).Example 330: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyethoxyindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-hydroxyethoxyindoline (25.2mg) obtained in Example 121 was dissolved in chloroform (5 ml). To theresultant solution was added activated manganese dioxide (138 mg). Theresulting suspension was stirred at room temperature for 22 hr, thenfiltered through celite and washed with chloroform. The filtrate wasconcentrated under reduced pressure and crystallized from ethylacetate/hexane to give the title compound (12.0 mg) as a white solid(yield: 48%).

¹H-NMR(400 MHZ,CDCl₃); δ(ppm) 2.05-2.13(4H,m), 2.22-2.30(2H,m),2.64(2H,t,J=7.5 Hz), 2.83(2H,t,J=7.5 Hz), 3.18(2H,br-d,J=12.1 Hz),4.00(2H,t,J=4.6 Hz), 4.09-4.17(1H,m), 4.17(2H,t,J=4.6 Hz),6.46(1H,d,J=3.3 Hz), 6.80(1H,dd,J=8.6,2.2 Hz), 6.88(1H,d,J=2.2 Hz),6.99(2H,t,J=8.4 Hz), 7.15(1H,d,J=3.3 Hz), 7.18(2H,dd,J=8.4,5.5 Hz),7.51(1H,d,J=8.6 Hz).m.p.: 118-119° C.Mass: FAB+383(M+H)+.Example 331: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-methanesulfonylindoline (19.2mg) obtained in Example 128 was dissolved in chloroform (5 ml). To theresultant solution was added activated manganese dioxide (100 mg). Theresulting suspension was stirred at room temperature for 22 hr and thenat 60° C. for additional 22 hr. After the completion of the reaction,the reaction mixtures were filtered through celite and washed withchloroform. The filtrate was concentrated under reduced pressure andcrystallized from ethyl acetate/hexane to give the title compound (5.0mg) as a white solid (yield: 26%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.06-2.24(4H,m), 2.32(2H,td,J=11.6,2.0Hz), 2.66(2H,t,J=7.2 Hz), 2.83(2H,t,J=7.2 Hz), 3.19(2H,br-d,J=9.9 Hz),4.33-4.42(1H,m), 6.64(1H,d,J=3.3 Hz), 6.99(2H,t,J=8.8 Hz),7.19(2H,dd,J=8.8,5.5 Hz), 7.49(1H,d,J=3.3 Hz), 7.61(1H,dd,J=7.3,1.1 Hz),7.77(1H,d,J=7.3 Hz), 8.04(1H,br-s).m.p.: 133-135° C.Mass: FAB+401(M+H)+.Example 332: Synthesis of1-[1-(2,6-difluoro-3-pyridylethyl)piperidin-4-yl]indole

1-[1-(2,6-Difluoro-3-pyridylethyl)piperidin-4-yl]indoline (30.5 mg)obtained in Example 57 was dissolved in chloroform (5 ml). To theresultant solution was added activated manganese dioxide (185 mg). Theresulting suspension was stirred at room temperature for 22 hr, filteredthrough celite and washed with chloroform. The filtrate was concentratedunder reduced pressure to give the title compound (27.4 mg) as an oil(yield: 90%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.00-2.15(4H,m), 2.28(2H,td,J=11.7,3.1Hz), 2.66(2H,t,J=8.1 Hz), 2.85(2H,t,J=8.1 Hz), 3.14(2H,br-d,J=11.7 Hz),4.24-4.30(1H,m), 6.52(1H,d,J=3.1 Hz), 6.79(1H,dd,J=8.1,2.7 Hz),7.10(1H,t,J=7.9 Hz), 7.21(1H,t,J=7.9 Hz), 7.23(1H,d,J=3.1 Hz),7.37(1H,d,J=7.9 Hz), 7.63(1H,d,J=7.9,5.3 Hz), 7.76(1H,dd,J=17.2,8.1 Hz).Mass; FAB+341(M+H).Example 333: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoroindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-fluoroindoline (28.8 mg)obtained in Example 103 was dissolved in chloroform (5 ml). To theresultant solution was added activated manganese dioxide (160 mg). Theresulting suspension was stirred at room temperature for 22 hr, filteredthrough celite and washed with chloroform. The filtrate was concentratedunder reduced pressure to give the title compound (20.1 mg) as an oil(yield: 70%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.04-2.15(4H,m), 2.26(2H,td,J=11.4,3.3Hz), 2.65(2H,t,J=8.8 Hz), 2.82(2H,t,J=8.8 Hz), 3.18(2H,br-d,J=11.4 Hz),4.08-4.17(1H,m), 6.50(1H,d,J=3.3 Hz), 6.87(1H,td,J=8.8,1.6 Hz),6.99(2H,t,J=8.6 Hz), 7.03(2H,dd,J=10.4,1.6 Hz), 7.18(2H,dd,J=8.6,5.5Hz), 7.22(1H,d,J=3.3 Hz), 7.52(1H,dd,J=8.8,5.3 Hz).Mass; FAB: 340(M+H)+.Example 334: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]thiazolo[5,4-f]indole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]thiazolo[5,4-f]indoline (23.7 mg)obtained in Example 234 was dissolved in chloroform (5 ml). To theresultant solution was added activated manganese dioxide (130 mg). Theresulting suspension was stirred at room temperature for 22 hr. Then thereaction mixtures were filtered through celite and washed withchloroform. The filtrate was concentrated under reduced pressure andcrystallized from ethyl acetate/hexane to give the title compound (12.6mg) as a pale yellow solid (yield: 53%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.07-2.18(4H,m), 2.24-2.35(2H,m),2.66(2H,t,J=7.0 Hz), 2.83(2H,t,J=7.0 Hz), 3.21(2H,br-d,J=12.1 Hz),4.36(1H,tt,J=11.7,4.4 Hz), 6.60(1H,d,J=3.5 Hz), 7.00(2H,t,J=8.6 Hz),7.19(2H,dd,J=8.6,5.5 Hz), 7.49(1H,d,J=3.5 Hz), 8.13(2H,s), 8.92(1H,s).m.p.: 152-154° C.Mass: FAB+380(M+H)+.Example 335: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylmethanesulfonylamino)indole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(N-methylmethanesulfonylamino)indoline(34.6 mg) obtained in Example 120 was dissolved in chloroform (5 ml). Tothe resultant solution was added activated manganese dioxide (190 mg).The resulting suspension was stirred at room temperature for 22 hr, thenfiltered through celite and washed with chloroform. The filtrate wasconcentrated under reduced pressure and crystallized from ethylacetate/hexane to give the title compound (24.7 mg) as a white solid(yield: 72%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.01-2.17(4H,m), 2.28(2H,td,J=11.7,3.3Hz), 2.65(2H,t,J=8.2 Hz), 2.83(2H,t,J=8.2 Hz), 2.88(3H,s),3.17(2H,br-d,J=12.1 Hz), 3.39(3H,s), 4.25(1H,tt,J=11.2,5.2 Hz),6.52(1H,d,J=3.3 Hz), 6.99(2H,t,J=8.6 Hz), 7.04(1H,dd,J=8.4,1.8 Hz),7.19(2H,dd,J=8.6,5.5 Hz), 7.30(1H,d,J=3.3 Hz), 7.47(1H,d,J=1.8 Hz),7.61(1H,d,J=8.4 Hz).m.p. 192-194° C.Mass: FAB+430(M+H)+.Example 336: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonyloxyindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-methanesulfonyloxyindoline(53.4 mg) obtained in Example 122 was dissolved in chloroform (5 ml). Tothe resultant solution was added activated manganese dioxide (300 mg).The resulting suspension was stirred at room temperature for 22 hr. Thenthe reaction mixtures were filtered through celite and washed withchloroform. The filtrate was concentrated under reduced pressure andcrystallized from ethyl acetate/hexane to give the title compound (40.0mg) as a white solid (yield: 75%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.87-2.01(4H,m), 2.22(2H,br-t,J=10.6Hz), 2.55(2H,t,J=7.9 Hz), 2.75(2H,t,J=7.9 Hz), 3.06(2H,br-d,J=11.2 Hz),3.34(3H,s), 4.32-4.41(1H,m), 6.50(1H,d,J=2.6 Hz), 6.98(1H,dd,J=8.4,1.5Hz), 7.09(2H,t,J=9.0 Hz), 7.27(2H,dd,J=9.0,5.7 Hz), 7.57(1H,d,J=1.5 Hz),7.56(1H,d,J=8.4 Hz), 7.60(1H,d,J=2.6 Hz).m.p.: 213-215° C.Mass: FAB+417(M+H)+.Example 337: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carbamoylindoline (14.1 mg)obtained in Example 125 was dissolved in chloroform (5 ml). To theresultant solution was added activated manganese dioxide (80 mg). Theresulting suspension was stirred at room temperature for 22 hr, thenfiltered through celite and washed with chloroform. The filtrate wasconcentrated under reduced pressure and crystallized from ethylacetate/hexane to give the title compound (5.0 mg) as a white solid(yield: 36%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.05-2.14(4H,m), 2.22-2.31(2H,m),2.62-2.67(2H,m), 2.78-2.84(2H,m), 3.18(2H,br-d, J=10.3 Hz),4.35-4.44(1H,m), 6.57(1H,d,J=3.3 Hz), 6.99(2H,t,J=8.2 Hz),7.18(2H,dd,J=8.2,5.3 Hz), 7.39(1H,d,J=3.3 Hz), 7.40(1H,d,J=8.1 Hz),7.64(1H,d,J=8.1 Hz), 8.10(1H,br-s).m.p.: 238-240° C.Mass: FAB+366(M+H)+.Example 338: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylsulfamoylmethyl)indole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(N-methylsulfamoylmethyl)indoline(30.4 mg) obtained in Example 164 was dissolved in chloroform (5 ml). Tothe resultant solution was added activated manganese dioxide (165 mg).The resulting suspension was stirred at room temperature for 22 hr. Thenthe reaction mixtures were filtered through celite and washed withchloroform. The filtrate was concentrated under reduced pressure andcrystallized from ethyl acetate/hexane to give the title compound (24mg) as a white solid (yield: 79%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.99-2.04(4H,m), 2.17-2.25(2H,m),2.54(2H,d,J=4.8), 2.55(2H,t,J=8.4 Hz), 2.76(2H,t,J=8.4 Hz),3.08(2H,br-d,J=11.7 Hz), 4.25-4.35(1H,m), 4.37(2H,s), 6.43(1H,d,J=3.1Hz), 6.83(1H,q,J=4.8 Hz), 7.01(1H,d,J=8.4 Hz), 7.09(2H,t,J=8.8 Hz),7.27(2H,dd,J=8.8,5.7 Hz), 7.50(1H,d,J=8.4 Hz), 7.51(1H,s),7.52(1H,d,J-3.1 Hz).m.p.: 172-175° C.Mass: FAB+430(M+H)+.Example 339: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-acetamidoindoline (32 mg)obtained in Example 115 was dissolved in chloroform (5 ml). To theresultant solution was added activated manganese dioxide (160 mg). Theresulting suspension was stirred at room temperature for 22 hr, thenfiltered through celite and washed with chloroform. The filtrate wasconcentrated under reduced pressure and crystallized from ethylacetate/hexane to give the title compound (23 mg) as a pale red solid(yield: 72%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.85-2.00(4H,m), 2.02(3H,s),2.13-2.23(2H,m), 2.55(2H,t,J=7.7 Hz), 2.75(2H,t,J=7.7 Hz),3.08(2H,br-d,J=11.7 Hz), 4.07-4.18(1H,m), 6.35(1H,d,J=2.2 Hz),7.05(1H,d,J=8.6 Hz), 7.09(2H,t,J=9.0 Hz), 7.27(2H,dd,J=9.0,6.0 Hz),7.39(1H,d,J=2.2 Hz), 7.40(1H,d,J=8.6 Hz), 7.92(1H,s), 9.85(1H,br-s).m.p.: 195-196° C.Mass: FAB+380(M+H)+.Example 340: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2-dihydroxypropan-3-yl)carbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.17 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.09 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, 1-amino-2,3-propanediol (0.40 g) dissolvedin N,N-dimethylformamide (1 ml) was added thereto and the mixture wasstirred for additional 7.5 hr. After evaporating the solvent underreduced pressure, water and ethyl acetate were added to the residue. Theorganic layer was separated, washed successively with water and brineand dried over magnesium sulfate. Then the solvent was evaporated underreduced pressure to give a pale brown viscous oil (0.14 g).

The resulting residue was dissolved in chloroform (30 ml) and manganesedioxide (0.27 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, additional manganese dioxide (0.13 g) was addedthereto followed by stirring for 3 hr. Next, the manganese dioxide wasfiltered off and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform/methanol system) to give a free title compound (0.07 g) as apale brown amorphous substance, which was then converted into an oxalatein a conventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.07(2H,br-d), 2.18-2.27(2H,m),2.84-3.06(7H,m), 3.17-3.28(3H,m), 3.45-3.53(3H,m), 3.53(2H,s),4.50-4.58(1H,m), 6.43(1H,d,J=3.2 Hz), 6.95(1H,d,J=8.8 Hz),7.16(2H,br-t), 7.32-7.36(2H,m), 7.41-7.46(3H,m), 7.99(1H,t,J=5.4 Hz).

ESI-Mass; 454(MH+).

Example 341: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(pyridin-2-yl)methylcarbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethyl-indoline (0.21g) obtained in Example 146 was dissolved in N,N-dimethylformamide (5ml). To the resultant solution was added 1,1-carbonyldiimidazole (0.11g) and the resultant mixture was stirred under nitrogen atmosphere atroom temperature for 15 min. Next, 2-aminomethylpyridine (287 ml) wasadded thereto and the mixture was stirred for additional 4 hr. Afterevaporating the solvent under reduced pressure, water and ethyl acetatewere added to the residue. The organic layer was separated, washedsuccessively with water and brine and dried over magnesium sulfate. Thenthe solvent was evaporated under reduced pressure to give a pale brownviscous oil (0.20 g).

The resulting residue was dissolved in chloroform (30 ml) and manganesedioxide (0.36 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, additional manganese dioxide (0.18 g) was addedthereto followed by stirring for 6 hr. Next, the manganese dioxide wasfiltered off and the solvent was evaporated under reduced pressure togive a free title compound (0.18 g) as a pale brown viscous oil, whichwas then converted into an oxalate in a conventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.09(2H,br-d), 2.25-2.34(2H,m),2.92-3.00(4H,m), 3.09-3.17(2H,m), 3.52(2H,br-d), 3.62(2H,s),4.37(2H,d,J=5.8 Hz), 4.54-4.64(1H,m), 6.45(1H,d,J=3.4 Hz),7.01(1H,d,J=8.0 Hz), 7.17(2H,br-t), 7.22-7.25(2H,m), 7.33-7.36(2H,m),7.42(1H,d,J=1.6 Hz), 7.48(1H,d,J=8.0 Hz), 7.50(1H,s), 7.68-7.72(1H,m),7.48(1H,d,J=3.4 Hz), 8.63(1H,t,J=5.8 Hz).ESI-Mass; 471(MH+).Example 342: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethylindole342-1) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-formylindoline (6.85 g)obtained in Example 348-3) was dissolved in methanol (50 ml) andtetrahydrofuran (25 ml), and the resultant solution was stirred underice cooling. Then sodium borohydride was added thereto in portions.After confirming the disappearance of the starting material by thinlayer chromatography, the solvent was evaporated under reduced pressureand ethyl acetate and an 8N aqueous solution of sodium hydroxide wereadded to the residue. The organic layer was separated, washedsuccessively with water and brine and dried over magnesium sulfate. Thenthe solvent was evaporated under reduced pressure to give the titlecompound (8.10 g) as colorless crystals.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.72-1.84(4H,m), 2.13-2.19(2H,m),2.60-2.64(2H,m), 2.84-2.88(2H,m), 2.93(2H,t,J=8.4 Hz), 3.13(2H,br-d),3.42(2H,t,J=8.4 Hz), 3.38-3.46(1H,m), 4.59(2H,s), 6.44(1H,s),6.57(1H,d,J=7.2 Hz), 6.99-7.04(2H,m), 7.04-7.08(1H,m), 7.16-7.23(2H,m).342-2) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline

Conc. hydrochloric acid (30 ml) was added to the1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline (7.49 g)obtained above and the resultant mixture was stirred at 80° C.overnight. Next, it was neutralized with a 5 N aqueous solution ofsodium hydroxide under ice cooling and then the pH value thereof wasadjusted to about pH 10 with a 10% aqueous solution of sodium carbonatefollowed by extraction with ethyl acetate. Then it was washed with brineand dried over magnesium sulfate. After evaporating the solvent underreduced pressure, the title compound (8.10 g) was obtained as pale browncrystals.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.72-1.85(4H,m), 2.14-2.21(2H,m),2.60-2.65(2H,m), 2.84-2.89(2H,m), 2.93(2H,t,J=8.4 Hz), 3.14(2H,br-d),3.37-3.44(1H,m), 3.43(2H,t,J=8.4 Hz), 4.52(2H,s), 6.40(1H,d,J=1.2 Hz),6.59(1H,dd,J=1.2,7.4 Hz), 6.99-7.04(2H,m), 7.05-7.09(1H,m),7.16-7.24(2H,m).342-3) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-cyanomethylindoline

Dimethyl sulfoxide (50 ml) was added to the1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (6.51 g)obtained above. After dissolving, sodium cyanide (0.94 g) was addedthereto and the resultant mixture was stirred at 50° C. for 2 hr. Thenice water was added thereto followed by extraction with ethyl acetate.Next, it was washed successively with a dilute aqueous solution ofsodium chloride and a saturated aqueous solution of sodium chloride anddried over magnesium sulfate. After evaporating the solvent underreduced pressure, the residue was purified by NH-silica gel columnchromatography (ethyl acetate/n-hexane system) to give the titlecompound (4.95 g) as a pale yellow viscous oil.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.72-1.83(4H,m), 2.14-2.21(2H,m),2.61(2H,m), 2.84-2.88(2H,m), 2.94(2H,t,J=8.4 Hz), 3.13(2H,br-d),3.35-3.44(1H,m), 3.44(2H,t,J=8.4 Hz), 3.65(2H,s), 6.30(1H,s),6.50(1H,d,J=7.2 Hz), 6.99-7.04(2H,m), 7.05-7.09(2H,m), 7.16-7.24(2H,m).342-4) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline

Water (10 ml) andconc. sulfuric acid (10 ml) were added to the1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-cyanomethylindoline (6.51 g)obtained above. After dissolution, the resultant mixture was heatedunder reflux. Then the reaction solution was ice-cooled and neutralizedwith an 8 N aqueous solution of sodium hydroxide and the pH value of themixture was adjusted to pH 6 with 1 N hydrochloric acid. Afterextracting with chloroform, it was washed with brine and dried overmagnesium sulfate. After evaporated the solvent under reduced pressure,the title compound (0.93 g) was obtained as a pale green powder.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.91-1.95(2H,m), 2.52(2H,br-s),2.80(2H,br-s), 2.90(2H,t,J=8.4 Hz), 3.13-3.17(2H,m), 3.27-3.31(2H,m),3.40(2H,t,J=8.4 Hz), 3.54-3.73(3H,m), 3.55(2H,s), 6.39(1H,s),6.55(1H,d,J=7.6 Hz), 6.97-7.13(3H,m), 7.25-7.35(2H,m).

ESI-Mass; 383(MH+).

342-5)1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-carboxymethyl-indoline (0.16g) obtained in Example 146 was dissolved in N,N-dimethylformamide (5ml). To the resultant solution was added 1,1-carbonyldiimidazole (0.08g) and the resultant mixture was stirred under nitrogen atmosphere atroom temperature for 15 min. Next, a 2 N solution (1.02 ml) ofmethylamine in tetrahydrofuran was added thereto and the resultantmixture was stirred for 2 hr. After evaporating the solvent underreduced pressure, water and ethyl acetate were added to the residue. Theorganic layer was separated, washed successively with water and brineand dried over magnesium sulfate. Then the solvent was evaporated underreduced pressure to give pale brown crystals (0.09 g).

The obtained crystals were dissolved in chloroform (20 ml) and manganesedioxide (0.20 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, additional manganese dioxide (0.20 g) was addedthereto followed by stirring for 7 hr. Next, the manganese dioxide wasfiltered off and the solvent was evaporated under reduced pressure. Theresidue was recrystallized from chloroform/n-hexane to give the titlecompound (0.06 g) as a pale brown powder.

m.p.: 136.5-137.4° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.08-2.13(4H,m), 2.28-2.35(2H,m),2.67-2.71(2H,m), 2.73(3H,d,J=4.8 Hz), 2.88-2.92(2H,m), 3.20(2H,br-d),3.72(2H,s), 4.21-4.28(1H,m), 5.40(1H,br-s), 6.53(1H,d,J=3.2 Hz),6.96(1H,dd,J=1.2,8.0 Hz), 7.01-7.06(1H,m), 7.06-7.10(1H,m),7.18-7.24(4H,m), 7.61(1H,d,J=8.0 Hz).ESI-Mass; 394(MH+).Example 343: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(1-acetylpiperidin-4-yl)methylcarbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.20 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.10 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, 1-acetyl-4-aminomethyl-piperidine (0.25 g)dissolved in N,N-dimethylformamide (1 ml) was added thereto and themixture was further stirred overnight. After evaporating the solventunder reduced pressure, water and ethyl acetate were added to theresidue. The organic layer was separated, washed successively with waterand brine and dried over magnesium sulfate. Then the solvent wasevaporated under reduced pressure to give a pale brown viscous oil (0.20g).

The resulting residue was dissolved in chloroform (30 ml) and manganesedioxide (0.33 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, additional manganese dioxide (0.17 g) was addedthereto followed by stirring for 6 hr. Next, the manganese dioxide wasfiltered off and the solvent was evaporated under reduced pressure togive the title compound (0.26 g) as a pale yellow amorphous substance.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 0.94-1.09(2H,m), 1.55-1.83(3H,m),2.04(3H,s), 2.08-2.13(4H,m), 2.25-2.31(2H,m), 2.46(1H,dt,J=2.4,12.8 Hz),2.64-2.68(2H,m), 2.81-2.85(2H,m), 2.92-3.03(2H, m), 3.11-3.20(3H,m),3.72(2H,s), 3.75(1H,br-d), 4.20-4.28(1H,m), 4.55(1H,br-d),5.55(1H,t,J=6.0 Hz), 6.53(1H,d,J=2.8 Hz), 6.95-7.01(3H,m),7.17-7.20(2H,m), 7.26-7.27(2H,m), 7.62(1H,d,J=8.0 Hz).ESI-Mass; 519(MH+).Example 344: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-ethylcarbamoylmethylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.16 g)obtained in Example 342-4) was dissolved in N,N-dimethylformamide (5ml). To the resultant solution was added 1,1-carbonyldiimidazole (0.08g) and the resultant mixture was stirred under nitrogen atmosphere atroom temperature for 15 min. Next, a 2 N solution (1.06 ml) ofethylamine in tetrahydrofuran was added thereto and the mixture wasfurther stirred for 2 hr. After evaporating the solvent under reducedpressure, water and ethyl acetate were added to the residue. The organiclayer was separated, washed successively with water and brine and driedover magnesium sulfate. Then the solvent was evaporated under reducedpressure to give pale brown crystals (0.11 g).

These crystals were dissolved in chloroform (20 ml) and manganesedioxide (0.23 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, additional manganese dioxide (0.23 g) was addedthereto followed by stirring for 7 hr. Next, the manganese dioxide wasfiltered off and the solvent was evaporated under reduced pressure. Theresidue was recrystallized from chloroform/n-hexane to give the titlecompound (0.07 g) as a pale brown powder.

m.p.: 147.0-148.6° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.02(3H,t,J=7.4 Hz), 2.08-2.13(4H,m),2.28-2.35(2H,m), 2.67-2.71(2H,m), 2.88-2.92(2H,m), 3.19-3.26(4H,m),3.70(2H,s), 4.21-4.29(1H,m), 5.40(1H,br-t), 6.53(1H,d,J=3.2 Hz),6.97(1H,dd,J=1.6,8.0 Hz), 7.01-7.06(1H,m), 7.06-7.10(1H,m),7.18-7.27(4H,m), 7.61(1H,d,J=8.0 Hz).ESI-Mass; 408(MH+).Example 345: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(1-ethylpiperidin-4-yl)methylcarbamoylmethylindoleoxalate345-1) 1-Acetyl-4-aminomethylpiperidine

Benzene (70 ml) was added to 4-aminomethylpiperidine (10.00 g) followedby dissolution. Next, benzaldehyde (9.30 g) was added thereto and theresultant mixture was heated under reflux for 3 hr with the use of aDean-Stark reflux condenser. After evaporating the solvent under reducedpressure, benzene (70 ml) was added to the residue followed bydissolution. Next, triethylamine (67 ml) and acetic anhydride (9.1 ml)were added thereto and the resultant mixture was stirred under nitrogenatmosphere at room temperature for 3 days. The solvent was evaporatedunder reduced pressure.

Sodium hydrogensulfate monohydrate (13.3 g) was dissolved in water (80ml) and the resulting residue was added thereto. The resultant mixturewas stirred at room temperature for 2.5 hr. Then the reaction solutionwas washed with ether. The aqueous layer was ice-cooled and the pH valuethereof was adjusted to pH 11 with a 5 N aqueous solution of sodiumhydroxide followed by extraction with chloroform under salting out. Thenthe extract was dried over magnesium sulfate and the solvent wasevaporated under reduced pressure to give the title compound (12.81 g)as a brown oil.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.04-1.19(2H,m), 1.50-1.57(1H,m),1.74-1.84(2H,m), 2.09(3H,s), 2.54(1H,dt,J=2.8,12.8 Hz), 2.62(2H,d,J=6.8Hz), 3.04(1H,dt,J=2.8,12.8 Hz), 3.80-3.86(1H,m), 4.61-4.67(1H,m).

345-2) 1-Ethyl -4-aminomethylpiperdine

Lithium aluminum hydride (1.06 g) was suspended in tetrahydrofuran (70ml) and the resultant suspension was stirred under nitrogen atmosphereunder ice cooling. Next, 1-acetyl-4-aminomethylpiperidine (4.14 g).dissolved in tetrahydrofuran (30 ml) was added thereto and the resultantmixture was stirred at room temperature for 10 min and heated underreflux overnight. Then the reaction mixtures were ice-cooled and water(1.06 ml), a 5 N aqueous solution of sodium hydroxide (1.06 ml) andfurther water (3.18 ml) were successively added thereto. After stirring,the mixture was diluted with ethyl acetate and the insolubles werefiltered off. The residue was purified by NH-silica gel columnchromatography (chloroform/methanol system) to give the title compound(3.15 g) as a pale brown oil.

345-3)1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(1-ethylpiperidin-4-yl)methylcarbamoylmethylindoleoxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.29 g)obtained in Example 146 was dissolved in N,N-dimethylformamide (5 ml).To the resultant solution was added 1,1-carbonyldiimidazole (0.15 g) andthe resultant mixture was stirred under nitrogen atmosphere at roomtemperature for 15 min. Next, 1-ethyl-4-aminomethylpiperidine (0.32 g)dissolved in N,N-dimethylformamide (1 ml) was added thereto and themixture was stirred for additional 3 hr. After evaporating the solventunder reduced pressure, water and ethyl acetate were added to theresidue. The organic layer was separated, washed successively with waterand brine and dried over magnesium sulfate. Then the solvent wasevaporated under reduced pressure to give a pale brown viscous oil (0.30g).

The obtained residue was dissolved in chloroform (30 ml) and manganesedioxide (0.51 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, additional manganese dioxide (0.51 g) was addedthereto followed by stirring for 13.5 hr. After further adding manganesedioxide (0.51 g), the resultant mixture was stirred overnight. Next, themanganese dioxide was filtered off and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol system) to give a free titlecompound (0.26 g) as a brown viscous oil, which was then converted intoan oxalate in a conventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.12(3H,t,J=6.6 Hz), 1.27-1.35(2H,m),1.54-1.64(1H,m), 1.73(2H,br-d), 1.92-2.08(4H,m), 2.30(2H,br-t),2.55(2H,br-t), 2.62-2.66(2H,m), 2.78-2.86(4H,m), 2.97(2H,br-t),3.14(2H,br-d), 3.23(2H,br-d), 3.50(2H,s), 4.26-4.34(1H,m),6.40(1H,d,J=3.2 Hz), 6.93(1H,d,J=8.0 Hz), 7.12(2H,br-t),7.28-7.32(2H,m), 7.41-7.45(2H,m), 8.09(1H,t,J=5.8 Hz).ESI-Mass; 505(MH+).Example 346: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(2-hydroxyethyl)carbamoylmethylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.20 g)obtained in Example 342-4) was dissolved in N,N-dimethylformamide (5ml). To the resultant solution was added 1,1-carbonyldiimidazole (0.10g) and the resultant mixture was stirred under nitrogen atmosphere atroom temperature for 15 min. Next, ethanolamine (161 ml) was addedthereto and the mixture was stirred overnight. After evaporating thesolvent under reduced pressure, water and ethyl acetate were added tothe residue. The organic layer was separated, washed successively withwater and brine and dried over magnesium sulfate. Then the solvent wasevaporated under reduced pressure to give pale brown crystals (0.14 g).

These crystals were dissolved in chloroform (30 ml) and manganesedioxide (0.28 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, the manganese dioxide was filtered off and thesolvent was evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate/n-hexane to give the title compound(0.07 g) as a pale gray powder.

m.p.: 127.7-128.6° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.08-2.21(4H,m), 2.31(2H,br-t),2.68-2.71(2H,m), 2.88-2.92(2H,m), 3.21(2H,br-d), 3.37(2H,dt,J=4.8,4.8Hz), 3.67(2H,t,J=4.8 Hz), 3.74(2H,s), 4.20-4.27(1H,m), 5.90(1H,br-s),6.51(1H,d,J=3.2 Hz), 6.96-7.10(3H,m), 7.18-7.26(3H,m), 7.32(1H,s),7.61(1H,d,J=8.0 Hz).ESI-Mass; 424(MH+).

Example 347: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,3-dioxolan-2-yl)methylcarbamoylmethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (0.22 g)obtained in Example 342-4) was dissolved in N,N-dimethylformamide (5ml). To the resultant solution was added 1,1-carbonyldiimidazole (0.11g) and the resultant mixture was stirred under nitrogen atmosphere atroom temperature for 15 min. Next, 2-aminomethyl-1,3-dioxolane (0.12 g)dissolved in N,N-dimethylformamide (1 ml) was added thereto and themixture was stirred overnight. After evaporating the solvent underreduced pressure, water and ethyl acetate were added to the residue. Theorganic layer was separated, washed successively with water and brineand dried over magnesium sulfate. Then the solvent was evaporated underreduced pressure to give pale brown crystals (0.20 g).

These crystals were dissolved in chloroform (20 ml) and manganesedioxide (0.38 g) was added thereto. After stirring the resultant mixtureat 50° C. overnight, additional manganese dioxide (0.38 g) was addedthereto and the mixture was stirred for 10.5 hr. Next, the manganesedioxide was filtered off and the solvent was evaporated under reducedpressure. The residue was recrystallized from chloroform/n-hexane togive the title compound (0.15 g) as colorless needles.

m.p.: 173.8-174.6° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.05-2.12(4H,m), 2.25-2.31(2H,m),2.64-2.68(2H,m), 2.81-2.85(2H,m), 3.18(2H,br-d), 3.43(2H,dd,J=3.6,6.0Hz), 3.73(2H,s), 3.75-3.79(4H,m), 4.21-4.29(1H,m), 4.90(1H,t,J=3.6 Hz),5.67(1H,t,J=6.0 Hz), 6.51(1H,d,J=3.2 Hz), 6.96-7.01(3H,m),7.17-7.20(2H,m), 7.25-7.28(2H,m), 7.60(1H,d,J=8.0 Hz).ESI-Mass; 466(MH+).Example 348: Synthesis of1-1-(2-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole348-1) 1-(2-Fluorophenethyl)piperidin-4-one

An aqueous solution (400 ml) of N,N-dimethyl-4-oxopiperidinium iodide(49.6 g) was added dropwise under reflux into a solution of2-fluorophenethylamine (25 g) and potassium carbonate (56.6 g) inwater(400 ml) andethanol (800 ml). After the completion of the addition, thereaction solution was further heated under reflux for 45 min. Thenethanol was evaporated under reduced pressure and the residue wasextracted with chloroform. The chloroform layer was washed with brineand dried over magnesium sulfate. After evaporating the solvent underreduced pressure, the residue was dissolved in a mixture of ethylacetate with chloroform (1:1) and filtered through silica gel. Thefiltrate was concentrated under reduced pressure to give the titlecompound (31.2 g) as ayellow oil (yield: 80.2%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.46-2.55(4H,m), 2.71-2.80(2H,m),2.80-2.93(6H,m), 6.98-7.10(2H,m), 7.16-7.25(2H,m).

348-2) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline

Triacetoxylated sodium borohydride (15.0 g) was added under ice coolingto a liquid mixture of 6-bromoindoline (9.0 g),1-(2-fluorophenethyl)piperidin-4-one (11.0 g) and acetic acid (12.5 ml)in 1,2-dichloroethane (140 ml). Then the reaction mixtures were stirredat room temperature overnight. The reaction mixtures were diluted withethyl acetate (400 ml) and then an 8 N aqueous solution (70 ml) ofsodium hydroxide was added thereto. The organic layer was separated,extracted with 5 N hydrochloric acid (100 ml) and then basified with an8 N aqueous solution of sodium hydroxide. Then it was extracted withethyl acetate and washed successively with water and brine. The ethylacetate layer was dried over magnesium sulfate and the solvent wasevaporated distilled off under reduced pressure to give the titlecompound (12.2 g) as a pale yellow solid (yield: 66.6%).2.10(2H,dt,J=7.6,2.8 Hz), 2.48-2.53(2H,m), 2.77(2H,t, J=8.4 Hz),2.83(2H,t,J=8.4 Hz), 2.96-3.03(2H,br-d), 3.37(2H,t,J=8.4 Hz),3.34-3.43(1H,m), 6.57(1H,d,J=1.2 Hz), 6.61(1H,dd,J=7.6,1.2 Hz),6.90(1H,d,J=7.6 Hz), 7.10-7.16(2H,m), 7.21-7.28(1H,m),7.33(1H,dt,J=7.6,1.2 Hz).

ESI-Mass; 404(MH+).

348-3) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-formylindoline

A 1.6 M solution (24 ml) of n-(butyllithium) in hexane was addeddropwise at −78° C. over 10 min into a solution of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (12 g) obtainedin Example 348-2) in tetrahydrofuran (200 ml). After 10 min,dimethylformamide (3.5 ml) was added thereto and the resultant mixturewas allowed to warm to room temperature. Then a saturated aqueoussolution (100 ml) of ammonium chloride and ethyl acetate (200 ml) wereadded thereto and the layers were separated. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting obtained was purifiedby silica gel column chromatography (ethyl acetate/ethanol system) togive the title compound (9.6 g) as a yellow powder (yield: 91.5%).

m.p.: 86-87° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.56-1.71(4H,m), 2.07-2.16(2H,m),2.48-2.56(2H,m), 2.77(2H,t,J=8.0 Hz), 2.94-3.06(4H,m), 3.39-3.50(3H,m),6.82(1H,s), 7.10-7.17(3H,m), 7.20-7.29(2H,m), 7.31-7.37(1H,m),9.83(1H,s).

ESI-Mass; 353(MH+).

348-4) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-formylindole

A suspension of 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-formylindoline(2.50 g) obtained in Example 348-3) and activated manganese dioxide (5.0g) in chloroform (100 ml) was heated under reflux for 4 hr undervigorous stirring. Further, activated manganese dioxide (5.0 g×1, 2.5g×2) was added to the reaction mixture at 1 hr intervals and theresultant mixture was reacted for additional 2 hr. The reaction solutionwas filtered through celite and the residue was washed with chloroform.The filtrate was concentrated under reduced pressure to give the titlecompound (1.94 g) as a yellow powder (yield: 78.0%).

m.p.: 128-1291° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.09-2.42(6H,m), 2.67-2.75(2H,m),2.83-2.91(2H,m), 3.19-3.28(2H,br-d), 4.35-4.45(1H,m), 6.61(1H,d,J=3.2Hz), 6.95-7.05(2H,m), 7.16-7.23(2H,m), 7.48(1H,d,J=3.2 Hz),7.62(1H,dd,J=8.0,1.2 Hz), 7.72(1H,d,J=8.0 Hz), 7.98(1H,s), 10.07(1H,s).Mass; 351(MH+).348-5) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole

A mixture of 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-formylindole(1.94 g) obtained in Example 348-4), hydroxylamine hydrochloride (0.5 g)and anhydrous sodium acetate (0.55 g) in methanol (60 ml) was stirred atroom temperature for 1 hr. Then the reaction mixtures were concentratedand the residue was partitioned between ethyl acetate (150 ml) and a 1 Naqueous solution (30 ml) of sodium hydroxide. The ethyl acetate layerwas washed successively with water and brine, dried over magnesiumsulfate and concentrated under reduced pressure to give1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindole (1.96g) as an ivory powder (yield: 96.8%).

A solution of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindole (1.95g) in tetrahydrofuran (50 ml) was added dropwise at room temperatureunder ice cooling and stirring into a suspension of lithium aluminumhydride (0.4 g) in tetrahydrofuran (100 ml). Then the resultant mixturewas heated under reflux for 3 hr. Under ice watar cooling, water (1 ml),a 5 N aqueous solution of sodium hydroxide (3 ml) and further water (1ml) were carefully added dropwise into the reaction mixtures and themixture was further vigorously stirred. The resulting precipitate wascollected by filtration and washed with tetrahydrofuran. The filtratewas concentrated under reduced pressure. The residue was purified byNH-silica gel column chromatography (ethyl acetate) to give the titlecompound (0.92 g) as a brown wax (yield: 49.1%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.80-2.04(4H,m), 2.22-2.30(2H,m),2.56-2.62(2H,m), 2.79-2.85(2H,m), 3.06-3.13(2H,m), 3.80(2H,s),4.27-4.38(1H,m), 6.38(1H,d,J=2.8 Hz), 6.97(1H,br-d), 7.12-7.18(2H,m),7.23-7.29(1H,m), 7.34-7.39(1H,m), 7.41-7.45(2H,m), 7.47(1H,br-s).Example 349: Synthesis of1-[1-(4-chlorophenethyl)piperidin-4-yl]-6-acetamidomethylindole

1-[1-(4-Chlorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline (120mg) obtained in Example 98, activated manganese dioxide (480 mg) andchloroform (10 ml) were treated as in Example 285 to give the titlecompound (95 mg) as a white powder (yield: 80 ).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.03(3H,s), 2.04-2.16(4H,m),2.24-2.40(2H,m), 2.64-2.76(2H,m), 2.81-2.95(2H,m), 3.12-3.29(2H,m),4.23-4.33(1H,m), 4.55(2H,d,J=5.6 Hz), 5.79(1H,br-s), 6.51(1H,d,J=3.6Hz), 7.03(1H,d,J=8.0 Hz), 7.17(2H,d,J=8.4 Hz), 7.25(1H,d,J=3.6 Hz),7.28(2H,d,J=8.4 Hz), 7.36(1H,s), 7.59(1H,d,J=8.0 Hz).m.p.: 148-149° C.Mass: FAB+410(M+H).Example 350: Synthesis of1-[1-(3-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole

1-[1-(3-Fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline (130mg) obtained in Example 135, activated manganese dioxide (520 mg) andchloroform (10 ml) were treated as in Example 285 to give the titlecompound (110 mg) as a white powder (yield: 85%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.03(3H,s), 2.04-2.16(4H,m),2.24-2.40(2H,m), 2.60-2.78(2H,m), 2.80-2.99(2H,m), 3.11-3.33(2H,m),4.22-4.33(1H,m), 4.55(2H,d,J=5.2 Hz), 5.78(1H,br-s), 6.51(1H,d,J=3.2Hz), 6.89-6.98(2H,m), 7.00-7.11(2H,m), 7.24-7.30(2H,m), 7.36(1H,s),7.59(1H,d,J=8.0 Hz).m.p.: 134-135° C.Mass: FAB+394(M+H).Example 351: Synthesis of1-[1-(4-methoxyphenethyl)-piperidin-4-yl]-6-acetamidomethylindole

1-[1-(4-Methoxyphenethyl)piperidin-4-yl]-6-acetamidomethylindoline (110mg) obtained in Example 97, activated manganese dioxide (440 mg) andchloroform (10 ml) were treated as in Example 285 to give the titlecompound (90 mg) as pale yellow prisms (yield: 82%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.03(3H,s), 2.05-2.15(4H,m),2.25-2.35(2H,m), 2.63-2.76(2H,m), 2.79-2.90(2H,m), 3.17-3.30(2H,m),3.80(3H,s), 4.22-4.31(1H,m), 4.52(2H,d,J=5.2 Hz), 5.73(1H,br-s),6.51(1H,d,J=3.6 Hz), 6.86(2H,d,J=8.4 Hz), 7.03(1H,d,J=8.0 Hz),7.16(2H,d,J=8.4 Hz), 7.25(1H,d,J=3.6 Hz), 7.36(1H,s), 7.59(1H,d,J=8.0Hz).m.p.: 101-102° C.Mass: FAB+406(M+H).Example 352: Synthesis of1-[F1-(2-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline (110mg) obtained in Example 134, activated manganese dioxide (440 mg) andchloroform (10 ml) were treated as in Example 285 to give the titlecompound (90 mg) as pale yellow needles (yield: 82%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.03(3H,s), 2.05-2.16(4H,m),2.31-2.43(2H,m), 2.69-2.82(2H,m), 2.86-2.99(2H,m), 3.17-3.31(2H,m),4.23-4.35(1H,m), 4.55(2H,d,J=5.6 Hz), 5.75(1H,br-s), 6.51(1H,d,J=3.6Hz), 6.99-7.13(3H,m), 7.15-7.27(3H,m), 7.37(1H,s), 7.59(1H,d,J=8.0 Hz).m.p.: 101-102° C.Mass: FAB+394(M+H).Example 353: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2,4-imidazolidinedion-3-yl)methylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(2,4-imidazolidinedion-3-yl)methylindoline(110 mg) obtained in Example 207, activated manganese dioxide (550 mg)and chloroform (10 ml) were treated as in Example 285 to give the titlecompound (80 mg) as a pale yellow powder (yield: 74%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.05-2.13(4H,m), 2.26-2.36(2H,m),2.63-2.70(2H,m), 2.80-2.87(2H,m), 3.14-3.20(2H,m), 3.93(2H,s),4.21-4.33(1H,m), 4.79(2H,s), 5.83(1H,br-s), 6.49(1H,d,J=3.2 Hz),6.96-7.03(2H,m), 7.15-7.22(3H,m), 7.25(1H,d,J=3.2 Hz), 7.48(1H,s),7.56(1H,d,J=8.0 Hz).m.p.: 156-157° C.Mass: FAB+435(M+H).Example 354: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isobutyrylaminomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-isobutyrylaminomethylindoline(110 mg) obtained in Example 158, activated manganese dioxide (550 mg)and chlorof orm (10 ml) were treated as in Example 285 to give the titlecompound (95 mg) as white needles (yield: 87%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.19(6H,d,J=7.6 Hz), 2.06-2.15(4H,m),2.26-2.43(2H,m), 2.38(1H,septet,J=7.6 Hz), 2.65-2.75(2H,m),2.81-2.91(2H,m), 3.18-3.27(2H,m), 4.22-4.31(1H,m), 4.56(2H,d,J=5.6 Hz),5.75(1H,br-s), 6.51(1H,d,J=3.2 Hz), 6.96-7.05(3H,m), 7.16-7.22(2H,m),7.25(1H,d,J=3.2 Hz), 7.33(1H,s), 7.59(1H,d,J=8.0 Hz).m.p.: 97-98° C.Mass: FAB+422(M+H).Example 355: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-imidazolidonyl)methylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(2-imidazolidonyl)methylindoline(80 mg) obtained in Example 206, activated manganese dioxide (400 mg)and chloroform (10 ml) were treated as in Example 285 to give the titlecompound (32 mg) as a pale yellow powder (yield: 48%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.04-2.18(4H,m), 2.28-2.42(2H,m),2.65-2.78(2H,m), 2.81-2.96(2H,m), 3.12-3.41(6H,m), 4.25-4.36(2H,m),4.49(2H,s), 6.52(1H,d,J=3.2 Hz), 6.99(1H,d,J=8.0 Hz), 7.00-7.09(2H,m),7.17-7.23(2H,m), 7.26(1H,d,J=3.2 Hz), 7.33(1H,s), 7.58(1H,d,J=8.0 Hz).m.p.: 130-131° C.Mass: FAB+421(M+H).Example 356: Synthesis of1-{1-[4-(4-fluorophenyl)butyl]-piperidin-4-yl}-6-acetamidomethylindole

1-{1-[4-(4-Fluorophenyl)butyl]piperidin-4-yl}-6-acetamidomethylindoline(110 mg) obtained in Example 227, activated manganese dioxide (550 mg)and chloroform (10 ml) were treated as in Example 285 to give the titlecompound (56 mg) as a white powder (yield: 51%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.62-1.72(4H,m), 2.04(3H,s),2.05-2.17(4H,m), 2.24-2.39(2H,m), 2.60-2.79(2H,m), 2.81-2.92(2H,m),3.10-3.22(2H,m), 4.23-4.35(1H,m), 4.55(2H,d,J=5.6 Hz), 5.83(1H,br-s),6.50(1H,d,J=3.2 Hz), 6.95-7.01(2H,m), 7.03(1H,d,J=8.0 Hz),7.12-7.17(2H,m), 7.23(1H,d,J=3.2 Hz), 7.26(1H,s), 7.58(1H,d,J=8.0 HZ).m.p.: 59-60° C.Mass: FAB+422(M+H).Example 357: Synthesis of1-[1-(2,4-difluorophenethyl)-piperidin-4-yl]-6-acetamidomethylindole

1-[1-(2,4-Difluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline(100 mg) obtained in Example 224, activated manganese dioxide (500 mg)and chloroform (10 ml) were treated as in Example 285 to give the titlecompound (83 mg) as an oil. This oil was then crystallized from ethylacetate by using oxalic acid (15 mg) to give the oxalate (46 mg) of thetitle compound as pale yellow prisms (yield: 42%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.00-2.28(4H,m), 2.05(3H,s),2.81-3.16(6H,m), 3.44-3.54(2H,m), 4.28(2H,d,J=5.2 Hz), 4.52-4.63(1H,m),6.47(1H,d,J=3.6 Hz), 6.99-7.16(3H,m), 7.32-7.40(1H,m), 7.44(1H,d,J=3.6Hz), 7.51-7.58(2H,m), 8.23(1H,t,J=5.2 Hz).

m.p.: 103-106° C.

Mass: FAB+412(M+H).

Example 358: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyrrolidon-1-yl)methylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(2-pyrrolidon-1-yl)methylindoline (80 mg) obtained in Example 202, activated manganesedioxide (400 mg) and chloroform (10 ml) were treated as in Example 285to give the title compound (69 mg) as an oil. This oil was thencrystallized from ethyl acetate by using oxalic acid (13 mg) to give theoxalate (54 mg) of the title compound as a white powder (yield: 61%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.83-1.92(2H,m), 2.05-2.25(4H,m),2.27(2H,t,J=8.0 Hz), 2.89-3.24(6H,m), 3.20(2H,t,J=8.0 Hz),3.46-3.56(2H,m), 4.44(2H,s), 4.54-4.66(1H,m), 6.45(1H,d,J=2.8 Hz),6.89(1H,d,J=8.0 Hz), 7.13-7.19(2H,m), 7.30-7.36(2H,m), 7.40-7.46(2H,m),7.50(1H,d,J=8.0 Hz).m.p.: 179-180° C.Mass: FAB+420(M+H).Example 359: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylacetamidomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-N-methylacetamidomethylindoline(140 mg) obtained in Example 163, activated manganese dioxide (700 mg)and chloroform (10 ml) were treated as in Example 285 to give the titlecompound (120 mg) as an oil. This oil was then crystallized from ethylacetate by using oxalic acid (24 mg) to give the oxalate (90 mg) of thetitle compound as a pale red powder (yield: 58%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.05(1.5H,s), 2.10(1.5H,s),2.05-2.26(4H,m), 2.78(1.5H,s), 2.87(1.5H,s), 2.90-3.04(4H,m),3.09-3.18(2H,m), 3.46-3.56(2H,m), 4.52-4.66(3H,m), 6.44(0.5H,d,J=2.8Hz), 6.47(0.5H,d,J=2.8 Hz), 6.86-6.92(1H,m), 7.13-7.20(2H,m),7.30-7.46(4H,m), 7.48(0.5H,d,J=8.0 Hz), 7.53(0.5H,d,J=8.0 Hz).m.p.: 148-149° C.Mass: FAB+408(M+H).Example 360: Synthesis of1-{1-[3-(4-fluorophenyl)propyl]-piperidin-4-yl}-6-acetamidomethylindole

1-{1-[3-(4-Fluorophenyl)propyl]piperidin-4-yl}-6-acetamidomethylindoline(110 mg) obtained in Example 226, activatedmanganese dioxide (550 mg)andchloroform (10 ml) were treated as in Example 285 to give the titlecompound (113 mg) as an oil. This oil was crystallized from diethylether with the use of oxalic acid (25 mg) to give the oxalate (90 mg) ofthe title compound as a pale red amorphous substance (yield: 67%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.84(3H,s), 1.87-1.97(2H,m),2.01-2.09(2H,m), 2.14-2.26(2H,m), 2.60-2.67(2H,m), 2.86-2.99(4H,m),3.41-3.50(2H,m), 4.32(2H,d,J=5.6 Hz), 4.53-4.61(1H,m), 6.43(1H,d,J=3.2Hz), 6.94(1H,d,J=8.0 Hz), 7.08-7.15(2H,m), 7.24-7.30(2H,m),7.39(1H,d,J=3.2 Hz), 7.40(1H,s), 7.47(1H,d,J=8.0 Hz), 8.30(1H,t,J=5.6Hz).Mass; FAB+408(M+H).Example 361: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylaminomethylindole

A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindole (400mg) obtained in Example 130, methylamine hydrochloride (150 mg), sodiumtriacetoxyborohydride (480 mg), acetic acid (300 mg) and dichioroethane(10 ml) was stirred at room temperature for 2 days. Then a saturatedaqueous solution of sodium bicarbonate and ethyl acetate were added tothe reaction mixtures. The organic layer was separated, washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting residue was purified by ChromatorexNH-silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (140 mg) as an oil. This oil was crystallizedfrom ethyl acetate by using oxalic acid (34 mg) to give the oxalate (140mg) of the title compound as a white powder (yield: 27%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.88-2.05(4H,m), 2.16-2.25(2H,m),2.41(3H,s), 2.53-2.60(2H,m), 2.73-2.78(2H,m), 3.04-3.12(2H,m),3.96(2H,s), 4.20(1H,br-s), 4.24-4.34(1H,m), 6.42(1H,d,J=3.2 Hz),7.02(1H,d,J=8.0 Hz), 7.06-7.13(2H,m), 7.25-7.30(2H,m), 7.49(1H,d,J=3.2Hz), 7.50(1H,d,J=8.0 Hz), 7.55(1H,s).m.p.: 195-196° C.Mass: FAB+366(M+H).Example 362: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-butyryl)aminomethylindole

A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole(200 mg) obtained in Example 322-3), n-butyric anhydride (158 mg) andpyridine (3 ml) was stirred at room temperature for 2 days. Then asaturated aqueous solution of sodium bicarbonate and ethyl acetate wereadded to the liquid reaction mixture. The organic layer was separated,washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (170 mg) as an oil. This oil was crystallizedfrom ethyl acetate by using oxalic acid (36 mg) to give the oxalate (170mg) of the title compound as a white amorphous substance (yield: 58%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 0.85(3H,t,J=7.2 Hz), 1.53(2H,q,J=7.2Hz), 1.98-2.18(6H,m), 2.69-3.02(6H,m), 3.35-3.44(2H,m), 4.34(2H,d,J=6.0Hz), 4.41-4.53(1H,m), 6.42(1H,d,J=3.2 Hz), 6.93(1H,d,J=8.4 Hz),7.10-7.18(2H,m), 7.27-7.35(2H,m), 7.39(1H,s), 7.42(1H,d,J=3.2 Hz),7.47(1H,d,J=8.4 Hz), 8.26(1H,t,J=6.0 Hz).Mass: FAB+422(M+H).Example 363: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyclopropanecarboxamidomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-cyclopropanecarboxamidomethylindoline(90 mg) obtained in Example 159, activated manganese dioxide (450 mg)and chloroform (10 ml) were treated as in Example 285 to give the titlecompound (60 mg) as a white powder (yield: 73%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 0.72-0.79(2H,m), 0.99-1.04(2H,m),1.31-1.42(1H,m), 2.05-2.17(4H,m), 2.22-2.35(2H,m), 2.63-2.75(2H,m),2.82-2.93(2H,m), 3.12-3.25(2H,m), 4.23-4.34(1H,m), 4.58(2H,d,J=5.6 Hz),5.89(1H,br-s), 6.51(1H,d,J=3.2 Hz), 6.97-7.03(2H,m), 7.06(1H,d,J=8.0Hz), 7.17-7.23(2H,m), 7.25(1H,d,J=3.2 Hz), 7.36(1H,s), 7.60(1H,d,J=8.0Hz).m.p.: 116-117° C.Mass: FAB+420(M+H).Example 364: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyacetamidomethylindole

A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole(150 mg) obtained in Example 322-3), acetoxyacetyl chloride (64 mg),pyridine (3 ml) and tetrahydrofuran (5 ml) was stirred under ice coolingfor 30 min. Then ice water and ethyl acetate were added to the reactionmixtures. The organic layer was separated, washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Tothe resulting residue were added methanol (10 ml) and potassiumcarbonate (100 mg) followed by stirring for 30 min. Then ice water andethyl acetate were added to the reaction mixtures. The organic layer wasseparated, washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate/ethanol system) togive the title compound (140 mg) as white scales (yield: 80%).

¹H-NMR(400 MHz,DMSO-d6); δ(ppm) 1.87-1.99(4H,m), 2.19-2.25(2H,m),2.52-2.59(2H,m), 2.72-2.78(2H,m), 3.03-3.11(2H,m), 3.82(2H,d,J=6.0 Hz),4.23-4.33(1H,m), 4.37(2H,d,J=6.0 Hz), 5.48(1H,t,J=6.0 Hz),6.38(1H,d,J=3.2 Hz), 6.95(1H,d,J=8.0 Hz), 7.06-7.13(2H,m),7.24-7.30(2H,m), 7.42(1H,d,J=8.0 Hz), 7.45(1H,d,J=3.2 Hz), 7.46(1H,s),8.14(1H,t,J=6.0 Hz).m.p.: 76-78° C.Mass: FAB+410(M+H).Example 365: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-difluoroacetamidomethylindole

Under ice cooling, N,N′-carbonyldiimidazole (160 mg) was added to asolution of difluoroacetic acid (96 mg) in dimethylformamide (5 ml) andthe resultant mixture was stirred for 30 min. Next, a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg)obtained in Example 322-3) in dimethylformamide (5 ml) was added theretoand the resultant mixture was stirred at room temperature for 2 hr. Thena saturated aqueous solution of sodium bicarbonate and ethyl acetatewere added to the reaction mixtures. The organic layer was separated,washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (120 mg) as a white powder (yield: 65%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.05-2.15(4H,m), 2.24-2.35(2H,m),2.63-2.70(2H,m), 2.79-2.86(2H,m), 3.14-3.22(2H,m), 4.20-4.30(1H,m),4.62(2H,d,J=5.6 Hz), 5.95(1H,t,J=54.2 Hz), 6.52(1H,d,J=3.6 Hz),6.61(1H,br-s), 6.96-7.02(2H,m), 7.03(1H,d,J=8.0 Hz), 7.15-7.21(2H,m),7.27(1H,d,J=3.6 Hz), 7.33(1H,s), 7.61(1H,d,J=8.0 Hz).m.p.: 79-80° C.Mass: FAB+430(M+H).Example 366: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoroacetamidomethylindole

Under ice cooling, ethyl chlorocarbonate (96 μl) was added to asuspension of sodium fluoroacetate (100 mg) in dimethylformamide (5 ml)and the resultant mixture was stirred for 20 min. Next, a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg)obtainedinExample 322-3) indimethylformamide (5 ml) was added theretoand the resultant mixture was stirred at room temperature for 2 hr. Thena saturated aqueous solution of sodium bicarbonate and ethyl acetatewere added to the reaction mixtures. The organic layer was separated,washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/ethyl acetate system) togive the title compound (100 mg) as a white powder (yield: 57%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.08-2.16(4H,m), 2.26-2.35(2H,m),2.64-2.71(2H,m), 2.81-2.88(2H,m), 3.16-3.24(2H,m), 4.21-4.31(1H,m),4.63(2H,d,J=5.6 Hz), 4.85(2H,d,J=47.6 Hz), 6.52(1H,d,J=3.2 Hz),6.60(1H,br-s), 6.96-7.02(2H,m), 7.04(1H,d,J=8.0 Hz), 7.16-7.21(2H,m),7.27(1H,d,J=3.2 Hz), 7.34(1H,s), 7.61(1H,d,J=8.0 Hz).m.p.: 106-108° C.Mass: FAB+412(M+H).Example 367: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-chloropropionylamino)methylindole

Under ice cooling, a mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg)obtained in Example 322-3), 3-chloropropionyl chloride (70 mg) andpyridine (5 ml) was stirred for 2 hr. Then a saturated aqueous solutionof sodium bicarbonate and ethyl acetate were added to the reactionmixtures. The organic layer was separated, washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(ethyl acetate/methanol system) to give the title compound (30 mg) as awhite powder (yield: 16%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.04-2.15(4H,m), 2.22-2.32(2H,m),2.62-2.69(2H,m), 2.65(2H,t,J=6.4 Hz), 2.80-2.87(2H,m), 3.13-3.22(2H,m),3.86(2H,t,J=6.4 Hz), 4.20-4.30(1H,m), 4.59(2H,d,J=5.6 Hz),5.99(1H,br-s), 6.51(1H,d,J=3.2 Hz), 6.97(1H,d,J=8.0 Hz),6.98-7.04(2H,m), 7.16-7.21(2H,m), 7.24(1H,d,J=3.2 Hz), 7.35(1H,s),7.58(1H,d,J=8.0 Hz).m.p.: 121-122° C.Mass: FAB+442(M+H).Example 368: Synthesis of1-[1--(4-fluorophenethyl)piperidin-4-yl]-6-imidazocarbonylaminomethylindole

Under ice cooling, N,N′-carbonyldiimidazole (160 mg) was added to asolution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole(150 mg) obtained in Example 322-3) in dimethylformamide (5 ml) and theresultant mixture was stirred for 30 min. Then ice water and ethylacetate were added to the reaction mixtures. The organic layer wasseparated, washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (ethyl acetate/ethanol system) togive the title compound (140 mg) as an oil. This oil was thencrystallized from ethyl acetate by using oxalic acid (28 mg) to give theoxalate (150 mg) of the title compound as a white powder (yield: 65%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.99-2.23(4H,m), 2.69-2.81(2H,m),2.84-3.02(4H,m), 3.33-3.43(2H,m), 4.47-4.57(1H,m), 4.54(2H,d,J=5.6 Hz),6.44(1H,d,J=2.8 Hz), 7.01(1H,s), 7.03(1H,d,J=8.0 Hz), 7.10-7.18(2H,m),7.27-7.35(2H,m), 7.45(1H,d,J=2.8 Hz), 7.51(1H,d,J=8.0 Hz), 7.53(1H,s),7.71(1H,s), 8.27(1H,s), 9.08(1H,t,J=5.6 Hz).m.p.: 156-157° C.Mass: FAB+446(M+H).Example 369: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-hydroxypropionylamino)methylindole

A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole(150 mg) obtained in Example 322-3), propiolactone (30 mg) and toluene(10 ml) was heated under reflux for 2 hr. Then the reaction solution wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate/ethanol system) to givethe title compound (150 mg) as an oil. This oil was then crystallizedfrom ethyl acetate by using oxalic acid (32 mg) to give the oxalate (100mg) of the title compound as a pale yellow amorphous substance (yield:45%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.03-2.25(4H,m), 2.29(2H,t,J=6.8 Hz),2.91-2.98(4H,m), 3.05-3.16(2H,m), 3.44-3.54(2H,m), 3.64(2H,t,J=6.8 Hz),4.35(2H,d,J=6.0 Hz), 4.50-4.60(1H,m), 6.43(1H,d,J=3.2 Hz),6.94(1H,d,J=8.4 Hz), 7.12-7.20(2H,m), 7.29-7.36(2H,m), 7.41(1H,d,J=3.2Hz), 7.43(1H,s), 7.46(1H,d,J=8.4 Hz), 8.28(1H,t,J=6.0 Hz).Mass; FAB+424(M+H).Example 370: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-formyl-6-acetamidomethylindole

Phosphorus oxychloride (0.1 g) was added at 0° C. to a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole (0.22 g)obtained in Example 285 in N,N-dimethylformamide (5 ml). The resultantmixture was stirred for 10 min and then reacted at 70° C. for 2 hr.After adding a 2 N aqueous solution of sodium hydroxide (20 ml), thereaction solution was extracted with ethyl acetate. The extract waswashed successively with water and brine, dried over magnesium sulfateand concentrated under reduced pressure. The resulting residue wasfiltered through silica gel (15 g) and washed with ethylacetate/methanol. The filtrate was concentrated to give the titlecompound (0.16 g) as a pale yellow amorphous substance (yield: 67.9%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.04(3H,s), 2.14-2.37(4H,m),2.37-2.49(2H,m), 2.73-2.82(2H,m), 2.87-2.95(2H,m), 3.25-3.35(2H,m),4.28-4.38(1H,m), 4.55(2H,d,J=5.6 Hz), 6.00-2.29(2H,t,J=6.8 Hz),2.91-2.98(4H,m), 3.05-3.16(2H,m), 3.44-3.54(2H,m), 3.64(2H,t,J=6.8 Hz),4.35(2H,d,J=6.0 Hz), 4.50-4.60(1H,m), 6.43(1H,d,J=3.2 Hz),6.94(1H,d,J=8.4 Hz), 7.12-7.20(2H,m), 7.29-7.36(2H,m), 7.41(1H,d,J=3.2Hz), 7.43(1H,s), 7.46(1H,d,J=8.4 Hz), 8.28(1H,t,J=6.0 Hz).Mass; FAB+424(M+H).Example 370: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-formyl-6-acetamidomethylindole

Phosphorus oxychloride (0.1 g) was added at 0° C. to a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole (0.22 g)obtained in Example 285 in N,N-dimethylformamide (5 ml). The resultantmixture was stirred for 10 min and then reacted at 70° C. for 2 hr.After adding a 2 N aqueous solution of sodium hydroxide (20 ml), thereaction solution was extracted with ethyl acetate. The extract waswashed successively with water and brine, dried over magnesium sulfateand concentrated under reduced pressure. The resulting residue wasfiltered through silica gel (15 g) and washed with ethylacetate/methanol. The filtrate was concentrated to give the titlecompound (0.16 g) as a pale yellow amorphous substance (yield: 67.9%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.04(3H,s), 2.14-2.37(4H,m),2.37-2.49(2H,m), 2.73-2.82(2H,m), 2.87-2.95(2H,m), 3.25-3.35(2H,m),4.28-4.38(1H,m), 4.55(2H,d,J=5.6 Hz), 6.00-6.12(1H,m), 6.97-7.04(2H,m),7.17-7.24(3H,m), 7.44(1H,br-s), 7.84(1H,s), 8.25(1H,d,J=8.0 Hz),9.97(1H,s).ESI-Mass; 422(MH+).Example 371: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-hydroxyimino-6-acetamidomethylindole

A liquid mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-formyl-6-acetamidomethylindole(0.09 g) obtained in Example 370, hydroxylamine hydrochloride (0.02 g)and anhydrous sodium acetate (0.03 g) in methanol (10 ml) was stirred atroom temperature for 1 hr. Then the reaction mixtures were concentratedand the residue was partitioned between ethyl acetate (20 ml) and a 1 Naqueous solution (10 ml) of sodium hydroxide. The ethyl acetate layerwas washed successively with water and brine, dried over magnesiumsulfate and concentrated under reduced pressure. Then the residue wascrystallized from ether/hexane, collected by filtration, washed withhexane and dried to give the title compound (0.08 g) as a pale yellowpowder (yield: 88.5%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.87(3H,s), 1.91-2.03(4H,m),2.20-2.30(2H,m), 2.56-2.62(2H,m), 2.74-2.80(2H,m), 3.06-3.3(2H,m),4.33-4.38(1H,m), 7.03-7.15(3H,m), 7.27-7.33(2H,m), 7.45-7.50(1H,m),7.77(1H,d,J=8.0 Hz), 7.83(0.5H,d,J=8.0 Hz), 7.91(0.5H,d,J=8.0 Hz),8.20(0.5H,s), 8.26(0.5H,s), 8.30-8.35(1H,m), 10.54(0.5H,s),11.27(0.5H,s).Example 372: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-hydroxymethyl-6-acetamidomethylindole

Sodium borohydride (0.01 g) was added to a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-formyl-6-acetamidomethylindole(0.04 g) obtained in Example 370 in methanol (10 ml) and the resultantmixture was stirred at room temperature for 0.5 hr. Then the reactionsolution was concentrated and the residue was partitioned between ethylacetate (40 ml) and water (10 ml). The ethyl acetate layer was washedsuccessively with water and brine, dried over magnesium sulfate andconcentrated under reduced pressure. Then the residue was treated withether/hexane to give the title compound (0.03 g) as a pale yellowamorphous substance (yield: 74.6%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.86(3H,s), 1.87-2.00(4H,m),2.18-2.27(2H,m), 2.54-2.61(2H,m), 3.05-3.12(2H,m), 4.22-4.32(1H,m),4.33(2H,d,J=5.6 Hz), 4.60(2H,d,J=5.6 Hz), 4.76(1H,t,J=5.6 Hz),6.94(1H,dd,J=8.0,1.2 Hz), 7.08-7.15(2H,m), 7.25-7.33(2H,m),7.36(1H,br-d), 8.26-8.32(1H,m).Example 373: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloroacetamidomethylindole

A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole(150 mg) obtained in Example 322-3), chloroacetyl chloride (60 mg),triethylamine (50 mg) and acetonitrile (5 ml) was stirred under icecooling for 2 hr. Then a saturated aqueous solution of sodiumbicarbonate and ethyl acetate were added to the reaction solution. Theorganic layer was separated, washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane/ethylacetate system) to give the title compound (90 mg) as white needles(yield: 49%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.06-2.13(4H,m), 2.24-2.33(2H,m),2.63-2.69(2H,m), 2.80-2.86(2H,m), 3.14-3.22(2H,m), 4.09(2H,s),4.20-4.30(1H,m), 4.59(2H,d,J=5.6 Hz), 6.52(1H,d,J=3.2 Hz),6.89(1H,br-s), 6.90-7.02(2H,m), 7.04(1H,d,J=8.0 Hz), 7.16-7.21(2H,m),7.26(1H,d,J=3.2 Hz), 7.33(1H,s), 7.61(1H,d,J=8.0 Hz).m.p.: 143-144° C.Mass: FAB+428(M+H).Example 374: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoacetamidomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (370 mg)obtained in Example 322-3), bromoacetyl chloride (220 mg), triethylamine(140 mg) and acetonitrile (10 ml) were treated as in Example 373 to givethe title compound (320 mg) as an oil (yield: 65%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.05-2.13(4H,m), 2.25-2.33(2H,m),2.62-2.70(2H,m), 2.79-2.85(2H,m), 3.15-3.24(2H,m), 3.92(2H,s),4.19-4.29(1H,m), 4.58(2H,d,J=5.6 Hz), 6.53(1H,d,J=3.2 Hz),6.90(1H,br-s), 6.92-7.04(3H,m), 7.15-7.21(2H,m), 7.25(1H,d,J=3.2 Hz),7.34(1H,s), 7.60(1H,d,J=8.0 Hz).Example 375: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N,N-dimethylaminoacetamido)methylindole

A mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoacetamidomethylindole(170 mg) obtained in Example 374, a 2 M solution (2.2 ml) ofdimethylamine in tetrahydrofuran and dimethylformamide (5 ml) wasstirred at room temperature for 2 hr. Then water and ethyl acetate wereadded to the reaction solution. The organic layer was separated, washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The resulting residue was purified byChromatorex NH silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (35 mg) as an oil.

This oil was crystallized from ethyl acetate by using oxalic acid (7 mg)to give the oxalate (18 mg) of the title compound as a white powder(yield: 9.4%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.96-2.16(4H,m), 2.39-2.44(2H,m),2.60(6H,s), 2.82-2.94(4H,m), 3.30-3.71(4H,m), 4.41(2H,d,J=5.6 Hz),4.42-4.52(1H,m), 6.43(1H,d,J=2.8 Hz), 6.96(1H,d,J=8.0 Hz),7.10-7.19(2H,m), 7.27-7.34(2H,m), 7.45(1H,s), 7.46(1H,d,J=2.8 Hz),7.49(1H,d,J=8.0 Hz), 8.53(1H,t,J=5.6 Hz).m.p.: 112-113° C.Mass: FAB+437(M+H).Example 376: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(piperidin-1-yl)acetamido]methylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoacetamidomethylindole(150 mg) obtained in Example 374, piperidine (187 mg) anddimethylformamide (5 ml) were treated as in Example 375 to give theoxalate (20 mg) of the title compound as a white powder (yield: 11 ).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.40-1.50(2H,m), 1.60-1.71(4H,m),2.00-2.08(2H,m), 2.12-2.26(2H,m), 2.37-2.52(2H,m), 2.70-3.10(8H,m),3.39-3.49(2H,m), 3.52-3.63(2H,m), 4.42(2H,d,J=6.0 Hz), 4.45-4.58(1H,m),6.43(1H,d,J=3.2 Hz), 6.96(1H,d,J=8.0 Hz), 7.10-7.19(2H,m),7.26-7.34(2H,m), 7.44(1H,d,J=3.2 Hz), 7.47(1H,s), 7.49(1H,d,J=8.0 Hz),8.76(1H,t,J=6.0 Hz).m.p.: 113-114° C.Mass: FAB+477(M+H).Example 377: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-bromopropionylamino)methylindole1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (370 mg)obtained in Example 322-3), 3-bromopropionyl chloride (240 mg),triethylamine (140 mg) and acetonitrile (10 ml) were treated as inExample 373 to give the title compound (290 mg) as an oil (yield: 57%).¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.02-2.10(2H,m), 2.14-2.26(2H,m),2.29-2.40(2H,m), 2.68-2.76(2H,m), 2.80(2H,t,J=6.4 Hz), 2.85-2.92(2H,m),3.18-3.26(2H,m), 3.70(2H,t,J=6.4 Hz), 4.20-4.30(1H,m), 4.62(2H,d,J=6.0Hz), 6.15(1H,br-s), 6.50(1H,d,J=3.2 Hz), 6.96-7.04(3H,m),7.16-7.24(2H,m), 7.25(1H,d,J=3.2 Hz), 7.37(1H,s), 7.58(1H,d,J=8.0 Hz).Example 378: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-N,N-dimethylaminopropionyl)aminomethylindole

A mixture of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-bromopropionylamino)methylindole(150 mg) obtained in Example 377, a 2 M solution (5.0 ml) ofdimethylamine in tetrahydrofuran and toluene (5 ml) was heated at 80 to90° C. for 1.5 days. Then water and ethyl acetate were added to thereaction mixtures. The organic layer was separated, washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was purified by Chromatorex NH-silicagel column chromatography (hexane/ethyl acetate system) to give thetitle compound (140 mg) as an oil. This oil was crystallized from ethylacetate by using oxalic acid (28 mg) to give the oxalate (110 mg) of thetitle compound as a white powder (yield: 66%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.90-1.99(2H,m), 2.00-2.12(2H,m),2.38-2.45(2H,m), 2.55(2H,t,J=7.2 Hz), 2.61(6H,s), 2.70-2.76(2H,m),2.78-2.85(2H,m), 3.11(2H,t,J=7.2 Hz), 3.16-3.24(2H,m), 4.37(2H,d,J=5.6Hz), 4.38-4.42(1H,m), 6.40(1H,d,J=2.8 Hz), 6.94(1H,d,J=8.0 Hz),7.08-7.14(2H,m), 7.25-7.32(2H,m), 7.42(1H,s), 7.45(1H,d,J=2.8 Hz),7.47(1H,d,J=8.0 Hz), 8.58(1H,t,J=5.6 Hz).m.p.: 104-105° C.Mass: FAB+451(M+H).Example 379: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[3-(piperidin-1-yl)propionylamino]methylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(3-bromopropionylamino)methylindole(140 mg) obtained in Example 377, piperidine (85 mg) and toluene (5 ml)were treated as in Example 378 to give the oxalate (80 mg) of the titlecompound as a white powder (yield: 44%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.39-1.49(2H,m), 1.57-1.66(4H,m),1.90-2.11(4H,m), 2.35-2.60(4H,m), 2.71-3.01(8H,m), 3.06-3.14(2H,m),3.18-3.25(2H,m), 4.36(2H,d,J=4.8 Hz), 4.37-4.45(1H,m), 6.41(1H,d,J=3.2Hz), 6.94(1H,d,J=8.0 Hz), 7.06-7.14(2H,m), 7.23-7.31(2H,m), 7.42(1H,s),7.45(1H,d,J=3.2 Hz), 7.47(1H,d,J=8.0 Hz), 8.56(1H,t,J=4.8 Hz).m.p.: 108-109° C.Mass: FAB+491(M+H).Example 380: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-propionylaminomethylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg)obtained in Example 348, propionyl chloride (43 mg), triethylamine (47mg) and acetonitrile (5 ml) were treated as in Example 373 to give thetitle compound (105 mg) as a white powder (yield: 60%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.19(3H,t,J=7.6 Hz), 2.00-2.16(4H,m),2.25(2H,q,J=7.6 Hz), 2.26-2.50(2H,m), 2.61-2.82(2H,m), 2.85-3.05(2H,m),3.20-3.34(2H,m), 4.19-4.33(1H,m), 4.56(2H,d,J=5.6 Hz), 5.75(1H,br-s),6.51(1H,d,J=3.2 Hz), 7.06-7.13(3H,m), 7.15-7.29(3H,m), 7.36(1H,s),7.59(1H,d,J=8.4 Hz).m.p.: 118-119° C.Mass: FAB+408(M+H).Example 381: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-fluoroacetamidomethylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg)obtained in Example 348, sodium fluoroacetate (100 mg), ethylchlorocarbonate (96 μl) and dimethylformamide (10 ml) were treated as inExample 373 to give the oxalate (100 mg) of the title compound as awhite powder (yield: 46%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 2.05-2.12(2H,m), 2.15-2.28(2H,m),2.93-3.05(4H,m), 3.09-3.17(2H,m), 3.49-3.58(2H,m), 4.41(2H,d,J=6.0 Hz),4.52-4.63(1H,m), 4.83(2H,d,J=47.2 Hz), 6.44(1H,d,J=3.2 Hz),6.98(1H,d,J=8.4 Hz), 7.15-7.22(2H,m), 7.27-7.35(1H,m), 7.36-7.46(3H,m),7.48(1H,d,J=8.4 Hz), 8.68(1H,t,J=6.0 Hz).m.p.: 168-169° C.Mass: FAB+412(M+H).Example 382: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(3-hydroxypropionylamino)methylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (110 mg)obtained in Example 348, β-propiolactone (23 mg) and toluene (10 ml)were treated as in Example 373 to give the title compound (90 mg) as awhite powder (yield: 69%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.99-2.06(4H,m), 2.28-2.39(2H,m),2.51(2H,t,J=5.2 Hz), 2.69-2.78(2H,m), 2.91-2.99(2H,m), 3.23-3.30(2H,m),3.95(2H,t,J=5.2 Hz), 4.14-4.24(1H,m), 4.63(2H,d,J=6.0 Hz),6.28(1H,br-s), 6.45(1H,d,J=3.2 Hz), 6.98(1H,d,J=8.8 Hz),7.02-7.12(2H,m), 7.14(1H,d,J=3.2 Hz), 7.19-7.27(2H,m), 7.57(1H,d,J=8.8Hz), 7.58(1H,s).m.p.: 58-59° C.Mass: FAB+424(M+H).Example 383: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxyacetamidomethylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg)obtained in Example 348 and acetoxyacetyl chloride (64 mg) were treatedas in Example 373 to give the title compound (110 mg) as a white powder(yield: 62%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.87-2.03(4H,m), 2.19-2.26(2H,m),2.54-2.60(2H,m), 2.76-2.83(2H,m), 3.04-3.11(2H,m), 3.82(2H,d,J=6.0 Hz),4.23-4.33(1H,m), 4.37(2H,d,J=6.0 Hz), 5.47(1H,t,J=6.0 Hz),6.38(1H,d,J=3.2 Hz), 6.95(1H,d,J=8.0 Hz), 7.10-7.17(2H,m),7.21-7.28(1H,m), 7.32-7.38(1H,m), 7.42(1H,d,J=8.0 Hz), 7.44(1H,d,J=3.2Hz), 7.45(1H,s), 8.14(1H,t,J=6.0 Hz).m.p.: 151-152° C.Mass: FAB+410(M+H).Example 384: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxycarbonylaminomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg)obtained in Example 322-3), methyl chlorocarbonate (47 mg),triethylamine (50 mg) andacetonitrile (5 ml) were treated as in Example373 to give the title compound (120 mg) as white needles (yield: 68%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.02-2.12(4H,m), 2.20-2.31(2H,m),2.60-2.68(2H,m), 2.78-2.85(2H,m), 3.12-3.20(2H,m), 3.70(3H,s),4.19-4.29(1H,m), 4.48(2H,d,J=6.0 Hz), 5.13(1H,br-s), 6.49(1H,d,J=3.2Hz), 6.95-7.01(2H,m), 7.03(1H,d,J=8.0 Hz), 7.15-7.20(2H,m),7.22(1H,d,J=3.2 Hz), 7.31(1H,s), 7.58(1H,d,J=8.0 Hz).m.p.: 117-118° C.Mass: FAB+410(M+H).Example 385: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N,N-dimethylaminocarbonylaminomethylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg)obtained in Example 322-3), dimethylcarbamyl chloride (54 mg),triethylamine (50 mg) and acetonitrile (5 ml) were treated as in Example373 to give the title compound (130 mg) as a white powder (yield: 72%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.04-2.11(4H,m), 2.23-2.30(2H,m),2.62-2.68(2H,m), 2.79-2.85(2H,m), 2.90(6H,s), 3.13-3.20(2H,m),4.20-4.30(1H,m), 4.53(2H,d,J=5.2 Hz), 4.70(1H,br-s), 6.49(1H,d,J=3.2Hz), 6.95-7.02(2H,m), 7.07(1H,d,J=8.0 Hz), 7.16-7.21(2H,m),7.23(1H,d,J=3.2 Hz), 7.35(1H,s), 7.58(1H,d,J=8.0 Hz).m.p.: 115-116° C.Mass: FAB+423(M+H).Example 386: Synthesis of1-{1-[2-(3-pyridyl)ethyl]-piperidin-4-yl}-6-acetamidomethylindole386-1) Synthesis of 1-(piperidin-4-yl)-6-acetamidomethyl-indole

1-(Piperidin-4-yl)-6-acetamidomethylindoline (0.6 g) obtained inProduction Example 52 and activated manganese dioxide (3.0 g) wereheated under reflux in chloroform (30 ml) for 8 hr. Then the reactionmixtures were filtered through celite. The residue was washed withchloroform and the filtrate was concentrated under reduced pressure. Theresulting residue was purified by NH-silica gel column chromatography(ethyl acetate/methanol system) to give the title compound (0.45 g) as abrown amorphous substance (yield: 75.5%).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.75-1.90(4H,m), 1.86(3H,s),2.64-2.74(2H,m), 3.04-3.10(2H,m), 4.30-4.39(1H,m), 4.33(2H,d,J=6.0 Hz),6.41(1H,d,J=3.0 Hz), 6.93(1H,dd,J=8.0,1.2 Hz), 7.41(1H,br-s),7.42(1H,d,J=3.0 Hz), 7.47(1H,d,J=8.0 Hz), 8.24-8.31(1H,m).

386-2) 1-{1-[2-(3-Pyridyl)ethyl]piperidin-4-yl}-6-acetamidomethylindole

Potassium carbonate (0.5 g) was added to a solution of1-(piperidin-4-yl)-6-acetamidomethylindole (0.10 g) obtained in Example386-1) and 3-(2-bromoethyl)pyridine (0.07 g) obtained in ProductionExample 26-2 in N,N-dimethylformamide (5 ml) and the resultant mixturewas stirred at 70° C. for 6 hr. Then the reaction mixtures wereconcentrated under reduced pressure and the residue was partitionedbetween ethyl acetate (40 ml) and water (15 ml) followed by extractionwith ethyl acetate. The ethyl acetate layer was washed with brine, driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform/methanol system) to give the title compound (0.06 g) as apale yellow wax (yield: 75.5%).

Then the obtained product was converted into an oxalate in aconventional manner to give the oxalate (0.06 g) of the title compoundas a pale yellow amorphous substance.

Oxalate:

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.87(3H,s), 2.00-2.09(2H,m),2.14-2.27(2H,m), 2.75-2.86(2H,m), 2.93-3.09(4H,m), 3.38-3.46(2H,m),4.35(2H,d,J=6.0 Hz), 4.47-4.60(1H,m), 6.44(1H,d,J=3.2 Hz),6.96(1H,d,J=8.0 Hz), 7.36(1H,dd,J=8.0,4.4 Hz), 7.43-7.47(2H,m),7.49(1H,d,J=8.0 Hz), 7.71-7.76(1H,m), 8.30-8.37(1H,m),8.46(1H,dd,J=8.0,1.6 Hz), 8.53(1H,d,J=1.6 Hz).ESI-Mass; 377(MH+).Example 387: Synthesis of 3-cyano-1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-acetamidomethylindole

1,1′-Carbonyldiimidazole (0.04 g) was added to a solution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-hydroxyimino-6-acetamidomethylindole(0.07 g) obtained in Example 371 in chloroform (10 ml) and the resultantmixture was stirred at room temperature for 0.5 hr. Then the reactionmixtures were concentrated and the residue was partitioned between ethylacetate (40 ml) and water (10 ml). The ethyl acetate layer was washedsuccessively with water and brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified byNH-silica gel column chromatography (ethyl acetate) to give the titlecompound (0.04 g) as a white powder (yield: 57.6%).

m.p.: 130-131° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.88(3H,s), 2.09-2.29(4H,m),2.82-3.14(6H,m), 3.42-3.52(2H,m), 4.39(2H,d,J=5.2 Hz), 4.64-4.74(1H,m),7.14-7.24(3H,m), 7.32-7.38(2H,m), 7.62(1H,d,J=8.4 Hz), 7.68(1H,s),8.43(1H,s).

Example 388: Synthesis of1-{4-[(1-hydroxyethyl)phenethyl]-piperidin-4-yl}-6-acetamidomethylindole

Potassium carbonate (0.5 g) was added to a solution of1-(piperidin-4-yl)-6-acetamidomethylindole (0.10 g) obtained in Example386-1) and 4-(1-hydroxyethyl)phenethyl bromide (0.07 g) obtained inProduction Example 19 in N,N-dimethylformamide (5 ml) and the resultantmixture was stirred at 70° C. for 6 hr. Then the reaction mixtures wereconcentrated under reduced pressure and the residue was partitionedbetween chloroform (40 ml) and water (15 ml). The chloroform layer waswashed with brine, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol system) to give the title compound(0.07 g) as a pale yellow wax (yield: 45.3%).

Then the resulting product was converted into an oxalate in aconventional manner to give the oxalate (0.06 g) of the title compoundas a pale yellow powder.

Oxalate:

m.p.: 105-107° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.31(2H,d,J=6.4 Hz), 1.87(3H,s),2.09-2.17(2H,m), 2.30-2.43(2H,m), 2.99-3.05(2H,m), 3.16-3.33(4H,m),3.62-3.70(2H,m), 4.35(2H,d,J=6.0 Hz), 4.64-4.74(2H,m), 6.47(1H,d,J=3.2Hz), 6.97(1H,d,J=8.0 Hz), 7.25(2H,d,J=8.0 Hz), 7.32(2H,d,J=8.0 Hz),7.43(1H,d,J=3.2 Hz), 7.48(1H,br-s), 7.50(1H,d,J=8.0 Hz),8.33-8.38(1H,m).ESI-Mass; 420(MH+).Example 389: Synthesis of 1-[1-(4-bromophenethyl)piperidin-4-yl]-6-acetamidomethylindole

Potassium carbonate (1.0 g) was added to a solution of1-(piperidin-4-yl)-6-acetamidomethylindole (0.20 g) obtained in Example386-1) and 4-bromophenethyl bromide (0.16 g) obtained in ProductionExample 4 in N,N-dimethylformamide (15 ml) and the resultant mixture wasstirred at 70° C. for 6 hr. Then the reaction mixtured were concentratedunder reduced pressure and the residue was partitioned betweenchloroform (40 ml) and water (15 ml). The chloroform layer was washedwith brine, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform/methanol system) and then crystallized from ethylacetate/hexane to give the title compound (0.25 g) as a pale yellowpowder (yield: 74.6%).

m.p.: 140-141° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.86(3H,s), 1.88-2.03(4H,m),2.19-2.28(2H,m), 2.56-2.62(2H,m), 2.73-2.79(2H,m), 3.05-3.12(2H,m),4.26-4.35(1H,m), 4.34(2H,d,J=6.0 Hz), 6.41(1H,d,J=3.2 Hz),6.97(1H,d,J=8.0 Hz), 7.25(2H,d,J=8.0 Hz), 7.32(2H,d,J=8.0 Hz),4.64-6.93(1H,dd,J=8.0,1.2 Hz), 7.23(2H,d,J=8.0 Hz), 7.40(1H,br-s),7.45-7.50(4H,m), 8.25-8.31(1H,m).ESI-Mass; 455 (MH+).Example 390: Synthesis of1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-formylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoine (0.49 g)obtained in Example 342-1) was dissolved in chloroform (40 ml). To theresultant solution was added manganese dioxide (1.20 g) and theresultant mixture was stirred at 50° C. overnight. After addingadditional manganese dioxide (0.60 g), the mixture was further stirredfor 7 hr. After further adding manganese dioxide (0.60 g), the mixturewas stirred overnight. After furthermore adding manganese dioxide (0.60g), the mixture was stirred for 10 hr. After furthermore addingmanganese dioxide (0.60 g), the mixture was stirred overnight. Next, themanganese dioxide was filtered off and the solvent was evaporated underreduced pressure to give the title compound (0.40 g) as a pale yellowpowder.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.07-2.13(4H,m), 2.27-2.34(2H,m),2.67-2.71(2H,m), 2.87-2.91(2H,m), 3.19(2H,br-d), 4.32-4.40(1H,m),6.59(1H,d,J=3.2 Hz), 7.00-7.03(1H,m), 7.05-7.10(1H,m), 7.17-7.25(2H,m),7.46(1H,d,J=3.2 Hz), 7.61(1H,dd,J=0.8,8.0 Hz), 6.71(1H,d,J=8.0 Hz),7.97(1H,s), 10.06(1H,s).ESI-Mass; 351(MH+).Example 391: Synthesis of 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindole

1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-formylindole (0.21 g) obtainedin Example 348-4) was dissolved in methanol (10 ml) andtetrahydrofuran(5 ml) andthe resultant solution was stirred under ice cooling. Thensodium borohydride was added thereto in portions. After confirming thedisappearance of the starting material by thin layer chromatography, thesolvent was evaporated under reduced pressure. Then a 2 N aqueoussolution of sodium hydroxide was added to the residue followed byextraction with ethyl acetate. The extract was washed successively withwater and brine and dried over magnesium sulfate. After evaporating thesolvent under reduced pressure, the residue was recrystallized fromchloroform/n-hexane to give the title compound (0.17 g) as a colorlesspowder.

m.p.: 116.8-117.5° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.07-2.16(4H,m), 2.26-2.33(2H,m),2.66-2.70(2H,m), 2.87-2.91(2H,m), 3.19(2H,br-d), 4.23-4.31(1H,m),4.82(2H,s), 6.51(1H,d,J=3.6 Hz), 7.01-7.11(3H,m), 7.17-7.26(3H,m),7.43(1H,s), 7.61(1H,d,J=8.0 Hz).

ESI-Mass; 353(MH+).

Example392: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyethyl)indole oxalate

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.15 g)obtained in Example 130 was dissolved in tetrahydrofuran (5 ml) andstirred under ice cooling. To the resultant solution was added a 1.0 Msolution (0.5 ml) of methylmagnesium bromide in ether and the mixturewas stirred for 30 min. Then a saturated aqueous solution of ammoniumchloride, water and ethyl acetate were added to the reaction solution.The organic layer was separated, washed successively with water andbrine and dried over magnesium sulfate. After evaporating the solventunder reduced pressure, a free title compound (0.13 g) was obtained as apale brown viscous oil, which was then converted into an oxalate in aconventional manner.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.38(3H,d,J=6.4 Hz), 2.10(2H,br-d),2.24-2.33(2H,m), 2.98-3.02(2H,m), 3.06(2H,br-t), 3.16-3.20(2H,m),3.56(2H,br-d), 4.63-4.70(1H,m), 6.44(1H,d,J=3.2 Hz), 7.03(1H,d,J=8.4Hz), 7.18(2H,br-t), 7.34-7.37(2H,m), 7.41(1H,d,J=3.2 Hz),7.47(1H,d,J=8.4 Hz), 7.53(1H,s).ESI-Mass; 367(MH+).Example 393: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ureidomethylindole

1,1-Carbonyldiimidazole (0.16 g) and imidazole (0.13 g) were added totetrahydrofuran (5 ml) and the resultant mixture was stirred undernitrogen atmosphere under ice cooling. Next,1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.33 g)obtained in Example 132 dissolved in tetrahydrofuran (3 ml) was addeddropwise thereinto. After stirring for 15 min, a saturated solution (2ml) of ammonia in ethanol was further added thereto and the resultantmixture was stirred under ice cooling for 10 min and then at roomtemperature overnight. Next, water and ethyl acetate were added to thereaction solution. The organic layer was separated, washed with brineand dried over magnesium sulfate. After evaporating the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (chloroform/methanol system) to give the title compoundas colorless crystals. Then these crystals were recrystallized fromchloroform/ethyl acetate/n-hexane to give the title compound (0.07 g) ascolorless needles.

m.p. 171.9-172.8° C.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.02-2.10(4H,m), 2.20-2.26(2H,m),2.60-2.64(2H,m), 2.78-2.82(2H,m), 3.12(2H,br-d), 4.16-4.24(1H,m),4.37(2H,d,J-5.4 Hz), 4.58(2H,s), 5.34(1H,t,J=5.4 Hz), 6.47(1H,d,J=3.2Hz), 6.96-7.00(3H,m), 7.15-7.18(2H,m), 7.21(1H,d,J=3.2 Hz), 7.29(1H,s),7.54(1H,d,J=8.0 Hz).ESI-Mass; 395(MH+).Example 394: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-methylureido)methylindole

1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.17 g)obtained in Example 132 was dissolved in tetrahydrofuran (5 ml) and theresultant solution was stirred under nitrogen atmosphere. After addingmethyl isothiocyanate (40.4 ml), the mixture was stirred for additional50 min. Then additional methyl isothiocyanate (40.4 ml) was addedthereto and the mixture was further stirred for 30 min. Afterevaporating the solvent under reduced pressure, the residue was purifiedby NH-silica gel column chromatography (ethyl acetate/n-hexane system)to give the title compound (0.14 g) as a pink amorphous substance.

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 2.07-2.12(4H,m), 2.26-2.33(2H,m),2.64-2.68(2H,m), 2.81-2.85(2H,m), 2.96(3H,br-d), 3.17(2H,br-d),4.22-4.30(1H,m), 4.71(2H,br-s), 5.87(1H,br-s), 6.09(1H,br-s),6.52(1H,d,J=3.2 Hz), 6.99(2H,br-t), 7.05(1H,d,J=8.0 Hz),7.17-7.20(2H,m), 7.27(1H,d,J=3.2 Hz), 7.37(1H,s), 7.61(1H,d,J=8.0 Hz).ESI-Mass; 425(MH+).Example 395: Synthesis of3,3-dimethyl-1-[1-(4-fluoro-phenethyl)piperidin-4-yl]-6-acetamidoindoline395-1)3,3-Dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline

Into a solution of3,3-dimethyl-1-[1-(4-fluoro-phenethyl)piperidin-4-yl]-6-bromoindoline(1.50 g) obtained in Example 293 in tetrahydrofuran (50 ml) was addeddropwise at −78° C. a 1.6 M solution (3 ml) of n-butyllithium in hexane.After 10 min, dimethylformamide (0.3 ml) was added thereto and theresultant mixture was warmed to room temperature. Then a saturatedaqueous solution of ammonium chloride (20 ml) and ethyl acetate (100 ml)were added thereto and the layers were separated. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. From the resulting residue,3,3-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline(0.68 g) was separated by silica gel column chromatography (ethylacetate). Then it was suspended in a solution of hydroxylammoniumchloride (0.15 g) and anhydrous sodium acetate (0.18 g) in ethanol (20ml) and stirred at room temperature for 2 hr. The reaction mixtures wereconcentrated under reduced pressure and diluted with ethyl acetate (50ml), a 2 N aqueous solution of sodium hydroxide (10 ml) and water (10ml). The organic layer was separated, washed with brine and dried overmagnesium sulfate. After evaporating the solvent, the obtained3,3-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindoline(0.55 g) was dissolved in tetrahydrofuran (5 ml). The resultant solutionwas added dropwise under ice cooling and stirring into a suspension oflithium aluminum hydride (0.07 g) in tetrahydrofuran (50 ml) and thenheated under reflux for 3 hr. Under ice water cooling, water (0.07 ml),a 5 N aqueous solution (0.21 ml) of sodium hydroxide and further water(0.07 ml) were carefully added dropwise into the reaction mixtures inthis order followed by vigorous stirring. The resulting precipitate wasfiltered off and the filtrate was concentrated under reduced pressure.The residue was purified by NH-silica gel column chromatography (ethylacetate/methanol system) to give the title compound (0.23 g) as a brownamorphous substance (total yield: 17.4%)

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.24(6H,s), 1.78-2.10(4H,m),2.38-2.51(2H,m), 2.72-2.83(2H,m), 2.89-2.98(2H,m), 3.17(2H,s),3.20-3.35(2H,m), 3.42-3.55(1H,m), 6.61(1H,s), 6.88(1H,d,J=8.0 Hz),6.94-7.01(3H,m), 7.14-7.20(2H,m).

395)-23,3-Dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline

Under ice cooling, acetyl chloride (0.05 ml) was added dropwise into asolution of3,3-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline(0.22 g) obtained above and triethylamine (0.5 ml) in tetrahydrofuran(10 ml) and the resultant mixture was stirred at room temperature for 1hr. Then a 1 N aqueous solution (5 ml) of sodium hydroxide and water (10ml) were added to the reaction mixture, which was extracted with ethylacetate, washed with brine and dried over magnesium sulfate. Afterevaporating the solvent, the residue was purified by silica gel columnchromatography (chloroform/methanol system) and crystallized from ethylacetate/hexane to give the title compound (0.18 g) as a yellowish whitepowder (yield: 73.7%).

m.p.: 131-133° C.

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.21(6H,s), 1.83(3H,s), 1.80-2.06(4H,m),2.98-3.20(4H,m), 3.07(2H,s), 3.21-3.42(2H,m), 3.58-3.68(1H,m),4.14(2H,d,J=6 Hz), 6.41(1H,s), 6.50(1H,br-d), 6.94(1H,br-d),7.14-7.22(2H,m), 7.28-7.38(2H,m), 8.17-8.21(1H,m).

ESI-Mass; 428(MH+).

Example 396: Synthesis of2,2-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline

396-1N-(1-Acetylpiperidin-4-yl)-3-methoxyaniline

Under ice cooling, sodium triacetoxyborohydride (12.0 g) was added to aliquid mixture of m-anisidine (4.40 g), 1-acetylpiperidin-4-one (5.0 g)and acetic acid (8 ml) in dichloroethane (80 ml). Then the reactionmixtures were stirred at room temperature overnight. The reactionmixtures were diluted with ethyl acetate (200 ml) and a 5 N aqueoussolution (35 ml) of sodium hydroxide was added thereto. The organiclayer was separated, washed successively with water and brine and driedover magnesium sulfate. After evaporating the solvent under reducedpressure, the residue was purified by silica gel column chromatography(ethyl acetate/hexane system) to give the title compound (7.80 g) as abrown oil (yield: 87.9%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.30-1.45(2H,m), 2.06-2.18(2H,m),2.11(3H,s), 2.76-2.85(1H,m), 3.13-3.22(1H,m), 3.43-3.51(1H,m),3.78(3H,s), 3.76-3.93(1H,m), 4.46-4.53(1H,m), 6.24(1H,br-s),6.28-6.36(2H,m), 7.11(1H,t,J=8.0 Hz).

396-2)N-(1-Acetylpiperidin-4-yl)-N-(2-methyl-2-propen-1-yl)-3-methoxyaniline

A mixture of N-(l-acetylpiperidin-4-yl)-3-methoxyaniline (2.0 g),3-chloro-2-methylpropene (10 ml) and potassium carbonate (5.0 g) indimethylformamide (50 ml) was reacted at 80° C. for 6 hr. Then thereaction mixtures were concentrated under reduced pressure andpartitioned between ethyl acetate and water. The ethyl acetate layer waswashed successively with water and brine and dried over magnesiumsulfate. After evaporating the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (ethylacetate/hexane system) to give the title compound (1.55 g) as a yellowoil (yield: 63.6%).

¹H-NMR(400 MHz,CDCl₃); δ(ppm) 1.46-1.60(2H,m), 1.73(3H,s),1.86-1.98(2H,m), 2.11(3H,s), 2.58(1H,dt,J=8.8,2.4 Hz),3.14(1H,dt,J=8.8,2.4 Hz), 3.59(2H,s), 3.77(3H,s), 3.80-3.94(2H,m),4.73-4.81(1H,s), 4.87(2H,d,J=9.2 Hz), 6.22-6.37(3H,m), 7.12(1H,t,J=8.0Hz).

396-3)2,2-Dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline

Under nitrogen atmosphere,N-(1-acetylpiperidin-4-yl)-N-(2-methyl-2-propen-1-yl)-3-methoxyaniline(1.50 g) was heated under reflux in the presence of zinc chloride (2.0g) in xylene (30 ml) for 4 hr. After cooling the reaction mixtures, a 5N aqueous solution (20 ml) of sodium hydroxide and ethyl acetate (100ml) were added thereto and the resultant mixture was stirred for 30 min.The ethyl acetate layer was separated, washed successively with waterand brine and dried over magnesium sulfate. After evaporating thesolvent, the residue was dissolved in ethanol (30 ml). Then a 5 Naqueous solution (10 ml) of sodium hydroxide was added thereto and themixture was heated under reflux for 2.5 hr. After concentrating themixture, the residue was partitioned between ethyl acetate and waterfollowed by extraction with ethyl acetate. The ethyl acetate layer waswashed with brine, dried over magnesium sulfate and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane system) to give a yellowoily mixture (0.91 g) containing2,2-dimethyl-1-(piperidin-4-yl)-6-methoxyindoline.

This mixture was reacted with 4-fluorophenethyl bromide (0.8 g) inN,N-dimethylf ormamide (20 ml) in the presence of potassium carbonate(1.5 g) at 70° C. for 6 hr. Then the reaction mixtures were concentratedunder reduced pressure and the residue was partitioned between water andethyl acetate followed by extraction with ethyl acetate. The ethylacetate layer was washed with brine, dried over magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby high performance liquid chromatography (ODS column,acetonitrile/water/70% perchloric acid system). After concentrating thesolvent, the residue was basified, extracted with ethyl acetate, washedwith water, dried and concentrated to give the title compound (0.31 g)as a pale yellow oil.

Next, this product was converted into an oxalate in a conventionalmanner to give a pale greenish blue powder.

Oxalate:

m.p.: 228° C. (decomp.).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.22(6H,s), 1.58-1.69(2H,m),2.50-2.75(4H,m), 2.94-3.11(4H,m), 3.15-3.25(2H,m), 3.36-3.61(3H,m),3.66(3H,s), 6.01(1H,d,J=8 Hz), 6.22(1H,s), 6.82(1H,d,J=8 Hz),7.14-7.24(2H,m), 7.30-7.38(2H,m).

ESI-Mass; 383(MH+).

Example 397: Synthesis of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-methylureido)methylindole

Under ice cooling, methyl isocyanate (0.02 g) was added dropwise into asolution of1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.09 g)obtained in Example 132 in ethyl acetate (10 ml) and the resultantmixture was stirred at room temperature for 1 hr. The resultingprecipitate was collected by filtration, washed with ether/hexane anddried to give the title compound (0.07 g) as a white powder (yield:67%).

m.p.: 192° C. (decomp.).

¹H-NMR(400 MHz,DMSO-d₆); δ(ppm) 1.88-2.04(4H,m), 2.19-2.27(2H,m),2.54-2.61(2H,m), 2.57(3H,d,J=4.4 Hz), 2.74-2.80(2H,m), 3.09(2H,br-d),4.25-4.34(1H,m), 4.28(2H,d,J=6.0 Hz), 5.73-5.78(1H,m), 6.26-6.32(1H,m),6.40(1H,d,J=3.2 Hz), 6.94(1H,d,J=8.0 Hz), 7.08-7.14(2H,m),7.27-7.32(2H,m), 7.39(1H,s), 7.44-7.48(2H,m).ESI-Mass; 409(MH+).

The Chemical formula of the compounds of Ex. 294 to 397 are cited below.

Referential Example 1: Synthesis of1-{1-[2-(5-oxo-7-methyl-5H-pyrimidinor[2,1][1,3]thiazol-6-yl)ethyl]piperidin-4-yl}indoline

[Co. No. 5 disclosed in WO96/23784]

1-[1-(2-Aminoethyl)piperazin-4-yl]indoline (192 mg) was dissolved in DMF(5 ml) and then7-methyl-6-(2-chloroethyl)-5H-pyrimidino[2,1-b][1,3]thiazol-5-one (239mg) and triethylamine (0.159 ml) were added thereto. Next, the resultantmixture was stirred at 80° C. for 11 hr and then at 100° C for 8 hr.After adding water, the reaction solution was extracted with ethylacetate. The organic layer was washed with brine and dried overmagnesium sulfate. After evaporating the solvent, the resulting residuewas purified by silica gel column chromatography (methanol/methylenechloride system) to give the title compound (46 mg) as an oil.

¹H-NMR (400 MHz, CDCl₃):

δ(ppm) 1.60-1.89(6H, m), 2.15-2.24(2H, m), 2.45(3H, s), 2.51-2.58(2H,m), 2.82-2.88(2H, m), 2.94(2H, t, J=8.2 Hz), 3.14-3.22(2H, m), 3.39(2H,t, J=8.2 Hz), 3.36-3.44(1H, m), 6.41(1H, d, J=7.6 Hz), 6.60(1H, t, J=7.6Hz), 6.92(1H, d, J=4.8 Hz), 7.01-7.07(2H, m), 7.91(1H, d, J=4.8 Hz).FAB-Mass: 395(MH+).

1. A compound of formula (I):

wherein A, B, C, D, and T are the same or different from one another andeach represents methine or nitrogen, provided that one and only one ofthem represents nitrogen; the bond represented by the following formula:- - - - - represents a single or double bond; Y and Z are the same ordifferent from each other and each represents methine, nitrogen, a grouprepresented by the following formula:

or a group represented by the following formula:

provided at least one of them represents nitrogen; R¹ and R² are thesame or different from each other and each represents hydrogen,halogeno, hydroxy, lower alkylsulfonylaminoalkyl, lowerhalogenated-alkylsulfonylaminoalkyl, 2-pyrrolidinon-1-yl, 1-hydroxy-1-(methoxypyridyl)methyl, methoxypyridylcarbonyl, 1,3-propanesultum-2-yl,lower hydroxypiperidyl -carbonylalkyl, lower hydroxyalkylamidoalkyl,lower halogenated-alkylamidoalkyl, lower dihalogenatedalkylamidoalkyl,lower hydroxyalkylamidoalkyl, optionally substituted amino, nitro, loweralkyl, lower alkoxy, lower acyl, lower alkoxyalkoxy, cyano, loweralkylsulfonyl, sulfonylamido, hydroxy-lower alkyl, hydroxy-lower alkoxy,lower alkoxycarbonylamino, lower alkylsulfonylamino, N-loweralkylalkylsulfonylamino, lower acylamino, optionally substitutedaminoalkyl, optionally N-substituted lower acylaminoalkyl, optionallysubstituted aryl, optionally substituted arylsulfonylamino, loweralkylsulfonyloxy, hydroxyiminomethyl, (2-pyrrolidonl-yl) methyl,(2-piperidon-1-yl) methyl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroarylalkyl,cycloalkylcarbonylaminoalkyl, optionally substituted ureido, optionallysubstituted ureido-lower alkyl, succinimido, (succinimido-1-yl)-loweralkyl, amido, optionally substituted carbamoyl, optionally substitutedcarbamoyl-lower alkyl, optionally substituted thiocarbamoyllower alkyl,formyl, aromatic acyl, heteroarylcarbonyl, halogenated lower alkyl,(2-imidazolidinon -1-yl)methyl, (2,4-imidazolidinedion-3-yl)methyl,(2-oxazolidon3-yl) methyl, (glutarimido-1-yl)methyl, optionallysubstituted heteroarylhydroxyalkyl, cyano-lower alkyl, 1-hydroxy lowercycloalkyl, (2,4-thiazolidinedion-3-yl)methyl, optionally substituted4-piperidylmethyl, heteroarylacyl, pyrrolidinylcarbonyl-lower alkyl,optionally substituted aminosulfonylalkyl, carboxy-lower alkyl, or loweralkylamidoalkyl; or alternatively optionally substituted heterocycle oralkylenedioxy, provided these rings may be substituted; R³ representshydrogen, halogeno, lower alkyl, hydroxy, hydroxy-lower alkyl, loweralkoxy, formyl, optionally substituted aralkyloxy, hydroxy-lower alkoxy,optionally substituted sulfamoyl, or optionally N-substitutedsulfamoyl-lower alkyl; R⁴ represents hydrogen, lower alkyl,hydroxy-lower alkyl, lower alkoxyalkyl, optionally aryl-substitutedaryloxyalkyl, or optionally aryl-substituted aralkyloxyalkyl; R⁵represents lower alkyl, lower acyl, lower alkoxycarbonyl, aromatic acyl,or a group represented by the following formula:-Q¹-(CH₂)_(s)-Q²-R⁶ wherein Q¹ and Q² are both single bonds, or one ofthem is a single bond while the other represents oxygen, carbonyl, agroup represented by —NHCO—, a group represented by —NHSO₂—, or a grouprepresented by >CH—R⁷, wherein R⁷ represents hydroxy, lower alkyl orhalogeno: s represents 0 or an integer of 1 to 6; and R⁶ representsoptionally substituted aryl, optionally substituted benzoheteroaryl,1,4-benzodioxanyl, 1,3-benzodioxolyl, benzothiazolyl, or cyano; nrepresents 1; m represents 0 or an integer of 1 to 6; and p representsan integer of 1 to 3, or a pharmacologically acceptable salt thereof. 2.A compound of formula:

wherein R represents a substituent of the formula:

wherein the bond represented by the following formula:- - - - - and R¹, R², R³, R⁴, R⁵, Y, Z, m, and p are each as defined inclaim 1, and pharmacologically acceptable salts thereof.
 3. The compoundof claim 1 or a pharmacologically acceptable salt thereof, wherein m is0 and p is
 2. 4. The compound of claim 1 or a pharmacologicallyacceptable salt thereof, wherein Y is methine and Z is nitrogen.
 5. Thecompound of claim 1 or a pharmacologically acceptable salt thereof,which is a compound selected from among the following ones: (267)1-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,(268)1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydro-quinoline,(269)1-[1-(4-cyanopropyl)piperidin-4-yl]-7-methoxy-1,2,3,4-tetrahydroquinoline,(270)1-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-1-7-methoxy-1,2,3,4-tetrahydroquinoline,(271) 1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7,8-dimethoxy-1,2,3,4-tetrahydroquinoline, (272)1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7,8-methylenedioxy-1,2,3,4-tetrahydroquinoline,(273)1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7-methoxy-8-methyl-1,2,3,4-tetrahydroquinoline,(274)1-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,(275)1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,(276)1-{1-[2-(4-fluorophenyl)-2-fluoroethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,and (283)5-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydroisoquiline.6. A pharmaceutical composition comprising a therapeutically effectiveamount of the compound of claim 1 or its salt in combination with apharmaceutically acceptable carrier.
 7. An agent for treating andameliorating diseases against which serotonin antagonism is efficacious,which contains as the active ingredient the compound of claim 1 or apharmacologically acceptable salt thereof.
 8. A compound for treatingand ameliorating spastic paralysis, which comprises as the activeingredient an effective amount of the compound of claim 1 or apharmacologically acceptable salt thereof.
 9. A muscle relaxantcomposition which contains as the active ingredient an effective amountof the compound of claim 1 or a pharmacologically acceptable saltthereof.
 10. A process for producing a compound of the formula:

wherein the bond represented by the following formula:----- and A, B, C, D, R¹, R², R³, R⁴, R⁵, n, and p are each as definedin claim 1, which comprises removing, if necessary, the protecting groupfrom a 1,4-substituted cyclic amine derivative (IX) represented by thefollowing formula:

wherein the bond represented by the following formula:----- and A, B, C, D, R¹, R², R³, R⁴, n, and p are each as defined inclaim 1; and Pr.G represents hydrogen or a protecting group, and thenreacting the same with L-R⁵ wherein R⁵ is as defined in claim 1; and Lrepresents a leaving group.
 11. A process for producing a compound ofclaim 1, which comprises reacting a fused cyclic amine represented bythe following formula:

wherein the bond represented by the following formula:----- and A, B, C, D, R¹, R², R³ and n are each as defined in claim 1with a cyclic ketone (VIII) represented by the following formula:

wherein R⁴, p, and Pr.G are each as defined in claim 1 in the presenceof a reducing agent to thereby give a 1,4-substituted cyclic aminederivative (IX), removing, if necessary, the protecting group therefromand further reacting the same with L-R⁵.
 12. A compound of the formula:

wherein the bond represented by the following formula:----- and A, B, C, D, R¹, R², R³, R⁴, n, and p are each as defined inclaim 1, provided that the case where R¹, R², R³ and R⁴ are all hydrogenatoms is excluded.
 13. A method for antagonizing serotonin, whichcomprises administering an effective dose of the compound of claim 1, ora pharmacologically acceptable salt thereof, to a person in need of suchtreatment.
 14. The compound of claim 1, in which the bond represented bythe following formula in the formula (I):----- is a single bond, represented by the formula (XXI)

or a pharmacologically acceptable salt thereof.
 15. The compound ofclaim 1, which m is 0 in the formula (I), represented by the formula(XXII)

or a pharmacologically acceptable salt thereof.
 16. The compound ofclaim 1, in which m is 1 to 6 in the formula (I) or a pharmacologicallyacceptable salt thereof.
 17. A compound of the formula (XXIII)

or a pharmacologically acceptable salt thereof.
 18. The compound ofclaim 1, in which the bond represented by the following formula in theformula (I):----- is a double bond, represented by the formula (XXIV):

or a pharmacologically acceptable salt thereof.
 19. The compound ofclaim 1, in which the T is nitrogen.